Immunotherapy: Using Your Own Cells to Fight Cancer - Part 2

 

By Gesa Junge, PhD

 

Part 1 of this post described passive immunotherapies like antibodies and cytokines, but there are also active immunotherapies, which re-target our immune system towards cancer cells, for example cancer vaccines. These can be preventative vaccines, offering protection against cancer-associated viruses such as Hepatitis B (liver cancer) or Human Papilloma Virus (HPV, cervical cancer). The link between HPV and cervical cancer was first described in 1983, and a vaccine was approved in 2006. By 2015, the incidence of HPV infections in women under 20 had decreased as much as 60% in countries that had 50% vaccination coverage, although it may still be too early to tell what the impact on HPV-associated cancer incidence is. There are also other factors to consider, for example screening programmes are also likely to have a positive impact on HPV-associated cancers.

Vaccines can also be therapeutic vaccines, which stimulate the immune system to attack cancer cells. To date, the only cancer vaccine approved in the US is Provenge, used for the treatment of metastatic prostate cancer. For this therapy, a patient’s white blood cells are extracted from the blood, incubated with prostatic acid phosphatase (PAP, a prostate-specific enzyme) and granulocyte macrophage colony stimulating factor (GM-CSF) in order to produce mature antigen presenting cells which are then returned to the patient and search and destroy tumour cells.

Many other therapeutic cancer vaccines are in development, for example OncoVax, which is an autologous vaccine made from a patient’s resected tumour cells. OncoVax has been in development since the 1990s and is currently in phase III trials. Another example is GVAX, an allogenic whole-cell tumour vaccine currently being studied in phase I and II trials or pancreatic and colorectal cancer. As an allogenic vaccine, it is not made from the patient’s own blood cells (like an autologous vaccine), and it does not target specific antigens but rather increases the production of cytokines and GM-CSF.

Another therapy which is based on re-programming the patient’s immune system is adoptive T-cell transfer. As with some cancer vaccines, a patient’s T-cells are isolated from the blood, and the cells with the greatest affinity for tumour cells are expanded in the lab and the re-infused in the patient. A recent modification of this technique is the use of chimeric antigen receptor (CAR) T-cells, where the T-cell receptors are genetically engineered to be more tumour-specific before re-infusion. This approached was especially promising in chronic lymphocytic leukaemia, where some patients experienced remissions of a year and longer. Later, CAR T-cells were also tested in acute lymphocytic leukaemia, where response rates were as high as 89%.

Finally, a new class of cancer drugs called immune checkpoint inhibitors has been making headlines recently, some of which are now approved for the treatment of cancer. Immune checkpoints are part of the mechanism by which human cells, including cancer cells, can evade the immune system. For example, the programmed cell death (PD) 1 receptor on immune cells interacts with PD1 ligand (PDL1) on cancer cells, which inhibits the killing of the cancer cell by the immune cell. Similarly, CTLA-4 is a receptor on activated T-cells which downregulates the immune response.

The first checkpoint inhibitor was an antibody to CTLA-4, ipilimumab, which was approved for the treatment of melanoma in 2011. PD1 antibodies such as pembrolizumab and nivolumab were only approved in 2014, and the only PDL1 antibody (atezolizumab) in 2016, so it is difficult to tell what the long-term effects of checkpoint inhibitor treatment will be. Numerous checkpoint inhibitors are still undergoing trials, most of the advanced (phase III) ones being targeted to PD1 or PDL1. However, there are other compounds in early trials (phase I or II) that target KIR (killer-cell immunoglobulin-like receptor) which are primarily being studied in myeloma, or LAG3 (lymphocyte activation gene 3), in trials for various solid tumours and leukaemias.

Immunotherapies all come under the umbrella of biological therapies. Biologics are produced by organisms, usually cells in a dish, unlike synthetic drugs, which are manufactured using a chemical process in the lab. This makes biologicals more expensive to manufacture. Ipilimumab therapy, for example, can cost about $100 000 per patient, with pembrolizumab and nivolumab being only slightly less expensive at $48 000 – $67 000. This puts considerable financial strain on patients and insurance companies. From a safety perspective, biologicals can cause the immune system to overreact. This sounds odd, as the whole point of immunotherapy is to activate the immune system in order to fight tumour cells, but if this response gets out of control, it can lead to potentially serious side effects as the immune system attacks the body’s organs and tissues.

All of these therapeutic approaches (antibodies, interleukins, vaccines, and checkpoint inhibitors) are usually not used alone but in combination with each other or other chemotherapy, which makes it difficult to definitively say which drug works best. But it is safe to say that collectively they have improved the lives of a lot of cancer patients. If you are interested in finding out more about the fascinating history of immunotherapy, from the discovery of the immune system to checkpoint inhibitors, check out the CRI’s timeline of progress on immunology and immunotherapy here.

 


Immunotherapy: Using Your Own Cells to Fight Cancer - Part 1

 

By Gesa Junge, PhD

 

Our immune system’s job is to recognize foreign, unfamiliar and potentially dangerous cells and molecules. On the one hand, it helps us fight infections by bacteria and viruses, while on the other hand it can leave us with annoying and potentially dangerous allergic reactions to harmless things like peanuts, pollen or pets. Tumor cells are arguably very harmful to our health, and yet the immune system does not always eliminate them. This is partially because cancer cells are our own cells, and not a foreign, unfamiliar intruder.

The immune system can recognize cancer cells; this was first postulated in 1909 by Paul Ehrlich and subsequently found by several others. However, detecting cancer cells may not be enough to prevent tumor growth. Recent research has shown that while detection can lead to elimination of cancer cells, some cells are not killed but enter an equilibrium stage, where they can exist undisturbed and undergo changes, and finally the cells can escape, if they have changed in a way that allows them to grow undetected by the immune system. This process of elimination, equilibrium and escape is referred to as “cancer immunoediting” and is one of the most active research areas in cancer, particularly in regard to cancer therapy.

Immunotherapy is a form of cancer therapy that harnesses our immune system to kill cancer cells, and there are various approaches to this. Probably the most established forms of immunotherapy are antibodies, which have been used for almost two decades. They generally target surface markers of cancer cells; for example, rituximab is an antibody to CD20, or trastuzumab, which targets HER2. CD20 and HER2 are cell surface proteins highly expressed by leukaemia and breast cancer cells, respectively, while normal, healthy cells have lower expression, making the cancer cells more susceptible. Rituximab was approved for Non-Hodgkins Lymphoma in 1997, the first of now nearly 20 antibodies to be routinely used in cancer therapy. In addition to this, there are several new antibodies undergoing clinical trials for most cancers. These are mainly antibodies to tumour-specific antigens (proteins that may only be expressed by e.g. prostate or lung cancer), and checkpoint inhibitors such as PD1 (more on that in part 2).

Initially, antibodies were usually generated in mice; however, giving murine antibodies to humans can lead to an immune response and resistance to the mouse antibodies when they are administered again later. Therefore, antibodies had to be “humanised”, i.e. made more like human antibodies, without losing the target affinity, and this was only made possible by advances in biotechnology. The first clinically used antibodies, such as rituximab, were chimeric antibodies, in which the variable region (which binds the target) is murine and the constant region is human, making them much better tolerated. Trastuzumab is an example of a humanised antibody, where only the very end of the variable region (the complementarity-determining region, CDR) is murine, and the rest of the molecule is human). And then there are fully human antibodies, such as panitumumab, an anti-EGFR antibody used to treat colorectal cancer. There is actually a system to labeling therapeutic antibodies: -ximab is chimeric, -zumab is humanised and –umab is human.

Antibodies can also be conjugated to drugs, which should make the drug more selective to its target and the antibody more effective in cell-killing. So far there are only very few antibody-drug conjugates in clinical use, but one example is Kadcyla, which consists of trastuzumab conjugated to emtansine, a cytotoxic agent.

Other examples of immunotherapy are cytokines such as interferons and interleukins. These are mediators of the immune response secreted by immune cells which can be given intravenously to help attack cancer cells, and they are used for example in the treatment of skin cancer. Interleukin 2 (IL-2) was the first interleukin to be approved, for the treatment of advanced melanoma and renal cancer, and research into new interleukins and their therapeutic potential is still going strong. Especially IL-2 and IL-12, but also several others are currently in clinical studies for both and various other indications, such as viral infections and autoimmune diseases.

In addition to passive immunotherapies like antibodies and cytokines, there are also active immunotherapies which re-target our immune system towards cancer cells, for example cancer vaccines. More on this, and on new drugs and their issues in part 2.

 

 

 


immune cells attack

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.


Fighting Zika Virus with Mosquito Genetics

 

By  John McLaughlin

 

The Zika virus burst into the news last year when a dramatic increase in microcephaly cases was reported throughout several states in Brazil. This frightening birth defect quickly became associated with the mosquito-borne virus, carried by Aedes mosquitos; Aedes aegypti, which also carries Dengue, is the main vector in the current Zika outbreak. While Zika virus usually affects adults with fairly mild symptoms such as fever, rash, and joint pain, it can have severe or fatal consequences for the fetuses being carried by infected females. In fact, The World Health Organization (WHO) has recently reported a scientific consensus on the theory that Zika is the cause of the large number of Brazilian microcephaly cases.

 

In January of 2016, a Hawaiian baby born with microcephaly became the first case of Zika reported in the United States. And the U.S. National Institute of Allergy and Infectious Diseases has recently stated that a wider outbreak of the virus within the United States will likely occur soon. Naturally, mosquito containment has become a top priority for health officials in both infected areas and those likely to be impacted by the virus. The standard list of mosquito control protocols includes pesticide repellents, mosquito nets, eliminating stagnant open water sources, and long-sleeved clothing to limit skin exposure. In addition to these, health authorities are considering a number of new strategies based on genetic engineering technologies.

 

One such technique employs the concept of gene drive, the fact that some “selfish” gene alleles can segregate into gametes at frequencies higher than the expected Mendelian ratios. In this scenario, gene drive can be exploited to spread a disease resistance gene quickly throughout a population of mosquitoes. Recently, a team at the University of California tested this idea by using CRISPR technology to engineer the mosquito Anopheles stephensi with a malarial resistance gene drive. After integration of the resistance gene cassette and DNA targeting with CRISPR, this gene was successfully copied onto the homologous chromosome with high efficiency, thus ensuring that close to 100% of its offspring will bear resistance. Possibly, similar techniques could be exploited to engineer Zika resistance in Aedes mosquitoes.

 

In contrast to engineering disease resistance, an alternative defense strategy is to simply reduce the population of a specific mosquito species, in the case of a Zika outbreak, Aedes aegypti. The WHO has recently approved a GM mosquito which, after breeding, produces offspring that die before reaching adulthood. This technique can dramatically reduce an insect population when applied in strategic locations. The British biotech firm Oxitech has also developed its own strain of sterile Aedes aegypti males. In laboratory testing, these GM mosquitoes compete effectively with wild males for female breeding partners. The short-term goal is receiving approval to test these sterile males in the wild; ultimately, a targeted release of these mosquitoes will reduce the Aedes aegypti population in Zika hot spots without affecting other species.

 

In parallel to mosquito engineering, other work has focused on studying the mechanisms underlying Zika’s dramatic affects on the brain. To study the process of Zika infection in vitro, scientists at Johns Hopkins cultured 3-D printed brain organoids and demonstrated that the virus preferentially infects neural stem cells, resulting in reduced cortical thickness owing to the loss of differentiated neurons. This neural cell death may explain the frequent microcephaly observed in fetuses carried by infected mothers.

 

Much like the recent outbreak of Ebola in several African countries, this event helps underscores the importance of basic research. A recent New York Times article drew attention to this fact by highlighting the need for more complete genome sequences of the mosquito species that carry Zika. With a complete genome sequence at hand, researchers might be able to piece together information in answering questions such as: why are some Aedes mosquitoes vectors for Zika and others aren’t? Species differences in genome sequence may provide some answers. Nevertheless, greater knowledge of the mosquito’s biology will yield more options for human intervention. This is an excellent case study in how ‘basic’ and ‘translational’ research projects can co-evolve in special situations.

 


RESIDENT LYMPHOCYTES KEEP A LOOKOUT FOR NASCENT CANCER CELLS

 

By Sophie Balmer, PhD

One of the first questions that comes to my mind when discussing the emergence of cancer cells is how my immune system recognizes that my own cells have been transformed? This process is commonly termed cancer immunosurveillance. In the prevalent model, the adaptive immune system composed of lymphocytes circulating in the blood stream plays the main function. However, recent findings describe specific immune cells already present within the tissue, a.k.a. tissue-resident lymphocytes, and how they trigger the first immune response against cancer cells, allowing a much faster reaction in an attempt to eradicate transformed cells.

 

The cancer immunosurveillance concept hypothesizes that sentinel thymus-derived immune cells constantly survey tissues for the presence of nascent transformed cells. Cancer immunosurveillance was first suggested in the early 1900’s by Dr. Erlich but it took another fifty years for Dr. Thomas and Dr. Burnet to revisit this model and speculate about the presence of transformed cells induced inflammation and antigen-specific lymphocyte responses. Additionally, Dr. Prehn and Dr. Main estimated that chemically-induced tumor triggered the synthesis of antigen at the surface of cancerous cells that could be recognized by the immune system. Countless studies arose from these hypotheses and either validated or disproved these models. The latest attempt was published a little over a month ago, in a paper by Dr. Dadi and colleagues, describing a new mechanism for the immune system to respond to nascent cancer lesions by activating specific resident lymphocytes.

 

In this study, the authors used a genetically-induced tumor model (the MMTV-PyMT spontaneous mammary cancer mouse model) to analyze the in vivo response of the immune system to nascent transformed cells. Most studies have been performed using chemically-induced tumors or tumor transplantation into a healthy host but these do not account for the initial environment of the nascent tumor. The spontaneous model the authors use rapidly exhibits developing cancer lesion (in 8-week old mice), allowing the analysis of cellular populations present near transformed cells.

 

To analyze which immune cell types are present near cancer lesions, the authors performed several analyses. First, they measure the levels of granzyme B, a serine protease found in granules synthesized by cytotoxic lymphocytes to generate apoptosis of targeted cells, and show that PyMT mice have elevated levels of granzyme B when compared to wild-type mouse. Moreover, similar analysis of PyMT secondary lymphoid organs show that this response was restricted to the transformed tissue.

During the first steps of immune responses, conventional natural killer (cNK) cells as well as innate lymphoid cells (ILC) are found in tumor microenvironments. In this model however, sorting of cells located in the vicinity of the lesion identified unconventional populations of immune cells, derived from innate, TCRab and TCRgd lineages. Indeed, their RNA-seq profiling reveal a specific gene signature characterized by high expression of the NK receptor NK1.1 but also the integrins CD49a and CD103. As these newly identified cells share part of their transcriptome with type 1 ILCs, the authors named them type 1-like ILCs (ILC1ls) and type 1 innate-like T cells (ILTC1s). In addition, transcripts encoding several immune effectors as well as apoptosis-inducing factors are upregulated in these cells, likely indicating that they trigger several pathways to eliminate transformed cells.

The authors also suggest that cNK cells are not required for immunosurveillance in this model and the unconventional lymphocytes described in this paper are regulated by the interleukine-15 (IL-15) in a dose-dependent way. Mice overexpressing IL-15 exhibit higher proliferation of these resident lymphocytes and tumor regression. Secretion of IL-15 in the tumor microenvironment might therefore promote cancer immunosurveillance.

 

In contradiction with the conventional view that recirculating populations of immune cells survey tissues for cellular transformation, ILC1ls and ILTC1s are tissue-resident lymphocytes. Their gene signature indicates that transcripts encoding motility-related genes are downregulated in these cells. Moreover, parabiosis experiments, during which two congenically marked mice are surgically united and share their blood stream, are performed to determine whether they are resident or circulating cells. The amounts of non-host ILC1s and ILTC1s are much reduced when compared to other recirculating immune cell type demonstrating that these cells are tissue-resident lymphocytes. Single-cell killing assays also determine that ILC1ls and ILTC1s are highly efficient at inducing apoptosis of tumor cells, which is more likely dependent on the lytic granules pathway.

 

Although the cancer immunosurveillance concept has been around for decades, it is still highly debated. Overall, these results shed light on this confusing field and bring up several questions. The signals recognized by this immune response are still unknown. Although the authors suggest that IL-15 might regulate the proliferation and/or activation of these cells, the source of IL-15 remains to be found. In addition, these cells might promote cancer immunosurveillance but are not sufficient to eradicate tumor cells and determining the cascade of signals induced by these resident lymphocytes will be required to ascertain their role. Establishing the limit of their efficiency as well as the mechanisms activated by transformed cell to escape their surveillance will also be crucial. Finally, one of the most important question to consider is how one could manipulate the activity of tissue-resident lymphocytes in cancer immunotherapy.


How Can You Make Money and Help Others with Your Shit?

And other very important poop updates.

 

By Jesica Levingston Mac leod, PhD

First, you have to be a healthy pooper… Second, you have to live in the Boston area. Your stool can help a person suffering from recurrent C. difficile infections, which is a bacterium that affects 500,000 Americans every year.  Where antibiotic treatment has failed to help, a new treatment called “fecal microbiota transplantation” has shown a cure rate of 90%.  In this procedure, a fecal microbiota preparation using stool from a healthy donor is transplanted into the colon of the patient.  OpenBiome, the startup company based in Boston, helps facilitate this procedure by screening and processing fecal microbiota preparations for use in this treatment. After joining the registration you and your stool will be screened and if you are healthy and a good candidate you will became a donor. If you can succeed with all the tests and you can provide “supplies” quite often then you can exchange money for you poo.

Lately, the study of the human microbiota has been all over the news, specially related with weight control, pregnancy and the infant’s diet. In fact, it's estimated that the human gut contains 100 trillion bacteria, or 10 times as many bacteria as cells in the human body. Yes, I know what you are thinking: “More of them that my own cells, that cannot be right, right?”

These bacteria, or microbiota, influence your health in many ways, from helping to extract energy from food to building the body's immune system, to protecting against infection with harmful, disease-causing bacteria.

Researchers are only just beginning to understand how differences in the composition of gut bacteria may influence human health. From what we know so far, here are five ways gut flora can affect your wellness:

 

Weight Changes

Yes, your gut bacteria affect your eating disorders (or orders if you are lucky). For example the diversity of gut bacteria is higher in lean people compared to obese people. Also, some specific bacteria groups, the Firmicutes and the Bacteroidetes, are linked with obesity. The famous study were they transplanted gut bacteria from obese and lean people to mice, making the host of the first kind of poo gain more weigh that the mice who received the “lean fecal bacteria”, was a shocking confirmation of the importance of the gut bacteria in the body weight regulation. They discovered that the gut bacteria from obese people increase the production of some amino acids, while the material from lean people increases the metabolism of “burning” carbohydrates.

 

Preterm Labor

Realman and col. found that pregnant women with lower levels of bacteria Lactobacillus in their vagina had an increased risk of preterm labor, compared with women whose vaginal bacterial communities were rich in Lactobacillus. Apparently, the absence of Lactobacillus allows the grown of other species that would have different effects in the pregnancy.

 

Crying Babies

In a funny study on how diet may affect babies, Pertty and col. showed that giving probiotics to your baby does not change the daily crying time, around 173 minutes, compare to the placebo group (174 min), according to the parental diary. They enrolled 30 infants with colic during the first 6 weeks of life.  However, parents reported a decrease of 68% in daily crying in the probiotic and 49% in the placebo group.

 

Heart Attacks

Gut Bacteria produce compounds can even affect your heart. One of these compounds is the trimethylamine-N-oxide (TMAO), and the presence of it in the blood of the subjects of a recent research study, increased 2.5 times the probability of having a heart attack, stroke or to die over a three-year period compared with people with low levels of TMAO. They have also shown that the metabolism of the gut bacteria changes according of the host’s (your) diet. For example, the consumption of high cholesterol and fatty food can increase the bacterial production of TMAO.

 

The Immune System

A recent review published in Cell rang the alarm about the negative effect of the “rich countries” diet in the microbiota influencing the immune system. In ideal and normal conditions the immune system-microbiota association allows the induction of protective responses to pathogens and the maintenance of regulatory pathways involved in the maintenance of tolerance to innocuous antigens. In rich countries, overuse of antibiotics, changes in diet, and elimination of constitutive partners, such as nematodes, may have selected for a microbiota that lack the resilience and diversity required to establish balanced immune responses. This phenomenon is proposed to account for some of the dramatic rise in autoimmune and inflammatory disorders in parts of the world where our symbiotic relationship with the microbiota has been the most affected.

 

Lungs and Asthma

The gut bacteria can affect your lungs: The low levels of 4 gut bacteria strains (FaecalibacteriumLachnospiraVeillonella, and Rothia) in kids was been recently related to an increase in the risk for developing debilitating asthma. The introduction of these 4 bacteria in mice induced to suffered asthma shown protection as the mice’s lungs did not present inflammation.

The question is: how bacteria IN the guts can affect your other tissues and organs? One study that was just published shows  that these bacteria produce chemicals that may help the immune system to battle against other germs. Without this training, the immune system could fail and create inflammation in the lungs. As a follow up from the latest research it may be possible in the near future to predict asthma, and other diseases, as well as cure some illnesses with gut bacteria.

Be ready to give a shit about your shit.


HPV vaccine now covers 9 strains

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.


Germs on the subway

Buggy Transportation

All the bugs in the metro, tube, subway, from NYC to Asia

By Jesica Levingston Mac leod, PhD

The New York City (NYC) subway is use for more than 5 million passengers per day. Passengers being humans, pets, bacteria, parasites, viruses and other unknown creatures. Consequently infectious diseases, like influenza can be easily transmitted in this transportation method. Other dangerous circumstances are the black carbon and particle matter concentrations, which In Manhattan are considerably higher than in the urban street level. If you have just ridden the subway, I recommend that you check you washed your hands before continue reading…because, literately, this article is about shit!

Last Month a great research team from Cornell published the studies on microorganisms from 466 subway stations where they found 76 known pathogens (aka “bad” bacteria), and, more interestingly, they found a lot of unknown organisms. This means that almost half of all DNA present on the subway’s surfaces matches no known organism. As they could identified some of the microorganisms, they described that these bacteria were originated in some metropolitan citizen food, pet, workplace… you can actually check which kind of bacteria was found in your favorite/closest subway station... just to be sure what to tell to your doctor next time that you have some infection….

During a year and a half, Dr. Mason, the leader of the group, took samples from materials like the metal handrails in order to collect DNA for the big data genetic metropolitan profile project, aka the Pathomap project. From the 15,152 types of life-forms, almost half of the DNA belonged to bacteria—most of them harmless; However, the scientists said the levels of bacteria they detected pose no public-health problem. The most prevalent bacterial species was Pseudomonas stutzeri, with enrichment in lower Manhattan (aka finance species ;)), followed by strains from Enterobacter and Stenotrophomonas. Notably, all of the most consistently abundant viruses (only 0.03%) were bacteriophages, which were detected concomitant with their bacterial hosts.

Other study done in 2013 in Norway, found that the airborne bacterial levels showed rapid temporal variation (up to 270-fold) on some occasions, both consistent and inconsistent with the diurnal profile. Airborne bacterium-containing particles were distributed between different sizes for particles of >1.1 μm, although ∼50% were between 1.1 and 3.3 μm. Anthropogenic activities (mainly human passengers) were the major sources of airborne bacteria and predominantly contributed 1.1- to 3.3-μm bacterium-containing particles. The peaks are at 8 am and 5 pm, following the rush hours.

Other great discovery was that the human allele frequencies in the subway mirrored US Census data. Within the neighborhoods they found African American and Yoruban alleles correlation for a mostly black area in Brooklyn, Hispanic/Amerindian alleles in the Bronx and they observed that Midtown Manhattan showed an increase in British, Tuscan, and European alleles.

In this globalized world, you won't be surprised that in the London's Tube a group of journalist and researchers found more than 3 million bacteria. These data suggested that the average train or bus seat could have more than 70 types of bacteria, plus cold and flu viruses. The North-South Victoria line was the only one that passed the hygiene test.

In a study at the Hong Kong subways system, researchers analyzed aerosol samples in order to find the taxonomic diversity of the "under" microbes. Each bacterial community within a line was dependent on architectural characteristics, nearby outdoor micro biomes, and distance to other lines, and were influenced by temperature and relative humidity.

Altogether these results sound really scary, but I hope that the reader won’t react panicking, but just being aware of the bad pathogens around him/her and carry a hand sanitizer/mask/cleaning aerosol/wipes or just wash your hands with soap! Actually, health officials from the FDA, believe washing hands with soap and water is the best method to get rid of germs.


Dengue It: Dengue-Specific Immune Response Offers Hope for Vaccine Design

 

By Asu Erden

The dengue virus is a mosquito-borne pathogen that infects between 50 and 100 million people every year. Furthermore, the World Health Organization estimates that approximately half of the global population is at risk. Yet there are currently neither vaccines nor medicines available against this disease, whose symptoms range from mild flu-like illness to severe hemorrhagic fever. The central challenge in designing a vaccine against dengue is that infection can be caused by any of four antigenically related viruses, also called serotypes. Moreover, prior infection with one serotype does not protect against the other three. In fact, such heterotypic exposure can result in much more severe secondary infections – a phenomenon called antibody-dependent enhancement. The lack of knowledge about naturally occurring neutralizing antibodies against dengue viruses has hindered the development of an efficient vaccine. A new study published in the journal Nature Immunology by Professor Screaton’s team at Imperial College, London, may allow the field to overcome this barrier.

 

In this month’s issue of Nature Immunology, Dejnirattisai and colleagues present their characterization of novel antibodies identified from seven hospitalized dengue patients. They first isolated monoclonal antibodies – antibodies made by identical immune cells derived from the same parent cell – from immune cells in the blood of these patients. Among the isolated antibodies, a group emerged that recognized a key component of the dengue virus envelope known as dengue E protein. But unlike previously identified antibodies, this group specifically recognized the envelope dimer epitope (EDE) of dengue, which results from the coming together of two envelope protein subunits on the mature virion rather than a single E protein.

 

The novelty of the study lies in its identification of a novel epitope – EDE – a potent immunogen capable of eliciting highly neutralizing antibodies against dengue. Previously identified antibodies did not show great efficacy against the virus. Antibodies that do not bind dengue antigens sufficiently strongly or are not present at a high enough concentration end up coating the virus through a process named opsonization. This is believed to lead to a more efficient uptake of the virus by immune cells thus fostering a more severe infection by infectious and sometimes also by non-infectious viral particles. This is the issue facing the field. An effective dengue vaccine would have to elicit a potent antibody response able to neutralize the virus while circumventing antibody-dependent enhancement. The antibodies characterized in this study present the peculiarity of efficiently neutralizing dengue virus produced in both insect cells and human cells – both relevant for the lifecycle of the virus – and being fully cross-reactive against the four serotypes.

 

The identification of highly neutralizing antibodies with an efficiency of 80-100%, cross-reactive against the dengue virus serocomplex, and able to bind both partially and fully mature viral particles offers hope for the design of a putative subunit vaccine. Mimicking potent immune responses seen in patients facilitates the process of vaccine development since it removes the need for identifying viral antigens relevant for protection not seen in nature. The naturally occurring responses already point in the right direction. Of the two dengue vaccine trials, neither relied on insight from such immune responses in patients infected with the virus. Based on the present study, it seems that the next step facing the field is to efficiently elicit an immune response that specifically targets EDE. If the antibodies identified here are shown to initiate protection in vivo, Dejnirattisai et al.’s study will have brought the field forward incommensurably.


You Can Help Cure Ebola!

 

By  Jesica Levingston Mac leod, PhD

Since the start of the outbreak last March, Ebola virus has already taken more than 8.000 lives and infected more than 21.200 people, according to the  Center for Disease Control (CDC). The panic raised from this situation rushed the testing of therapies to stop the outbreak and the research on the Ebola virus has seen a rebirth. Some research groups that have been working in this field for a long time can now openly ask for help. One of these groups is the one lead by Dr. Erica Ollman Shaphire at The Scripps Research Institute, California. In 2013 they published in Cell an analysis of the different conformations of Ebola VP40 (Viral Protein 40) aka the shape-shifting “transformer” protein. They reported 3 different conformations of this protein, and how this variety allows it to achieve multiple functions in the viral replication circle. This Ebola virus protein along with the glycoprotein would be used as target for anti viral research. In order to find new anti-virals, their approach is an in-silico scrutiny of thousands of compounds, using viral protein crystal structures in the in silico docking to find leads that may be tested in the lab as inhibitors. IBM is already helping them in this project, generating the World Community Grid to find drugs through the Outsmart Ebola Together project.  Here is where you can start helping, as this project involves a huge amount of data and computing time, they need volunteers that can donate their devices spare computing time (android, computer, kindle fire, etc) to generate a faster virtual supercomputer than can accelerate the discover of new potential drugs. This approach has been shown to be successful for other diseases like HIV and malaria, so you are welcome to join the fight against Ebola virus: https://secure.worldcommunitygrid.org/research/oet1/overview.do.

If you do not have any of these devices (I hope you are enjoying the public library free computers), you can still help Dr. Shapire quest to discover new therapies against Ebola. Her group is now “working to support the salary of a computer scientist to help process the data we are generating with the world community grid” as she describes it. To help identify the most promising drug leads for further testing you can donate money on: www.crowdrise.com/cureebola.

Other groups that were mostly working on other viruses, like Flu, also joined the race to discover efficient therapies. For example, last month, the Emerging Microbes and Infections journal of the Nature Publishing Group published the identification of 53 drugs that are potential inhibitors of the Ebola virus. One of the authors of this paper is Dr. Carles Martínez-Romero, from Dr. Adolfo García-Sastre’s lab in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai. In the study, Dr. Martínez-Romero and collaborators described how they narrowed the search from 2.816 FDA approved compounds to 53 potential antiviral drugs. This high-throughput screening was possible thanks to the use of the Ebola viral-like particle (VLP) entry assay. This allows studying Ebola viral entry without using the ”real”, full replicative virus. These 53 compounds blocked the entry of Ebola VLPs into the cell. Understanding how these market-ready compounds can inhibit Ebola entry and its infectious cycle will pave the way for a new generation of treatments against Ebola virus-associated disease.

Dr. Martínez-Romero had an early interest in science; “Since I was a child, I showed great interest in biological sciences and a great desire to question and discover. This led me to pursue my studies in Biotechnology in order to become a successful researcher.”Viruses are very interesting to me because, although they are not strictly living organisms, they are as old as life itself. Even though they are the origin of many illnesses in mammals and other organisms alike, we are tightly interconnected with viruses and they will continue shaping our evolution throughout the years to come.

I also asked him about advice to his fellow researchers, and he answered: “There is a famous quote of Dr. Albert Einstein: “If we knew what we were doing, it wouldn’t be called Research”. As postdocs and researchers in general, we are constantly pursuing new hypotheses. It is a very arduous path with its ups and downs but full of rewards and new challenges ahead.” About the future of the antiviral research, he keeps a positive view: “Several antiviral therapies are being developed to combat the current Ebola outbreak, such as antibody cocktails (Zmapp), antiviral drugs, and specific Ebola vaccines. Together with re-purposing screens like the one we published, a combination of therapeutic drugs can be used to obtain better antiviral strategies against the Ebola virus.”


MRSA vaccine

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.

 


How Our Environment Affects the Development of Autoimmune Diseases

 

By Asu Erden

In the past fifty years, there has been a significant increase in the incidence of autoimmune diseases, such as type 1 diabetes and lupus, in the West and in countries adopting western lifestyles. Given that half a century is too small a time scale for human evolution to occur, what exactly is contributing to this increase? Recent studies have been highlighting the role of environmental factors.

 

If the age-old debate regarding the relative importance of nature versus nurture taught us anything, it is that the more apt position lies somewhere in the middle. Both our genetic makeup and the environment in which we live affect our phenotype. However, the study of autoimmune diseases has often focused on the contribution of genetic factors. The etiology of these diseases relies on recognizing one’s own proteins – also called self-antigens – and on triggering an immune response against them. For such a response to occur, these antigens need to be presented to the immune system by genetically encoded molecules called human leukocyte antigen (HLA) molecules. They constitute the most highly associated factor with autoimmune diseases. It is therefore easy to overlook the role of the environment.

 

Two seminal studies have contributed to shifting this bias. The first by Mahdi and colleagues at the Karolinska Institute in Stockholm, Sweden, looks at the impact of smoking on the development of rheumatoid arthritis (RA). The other by Dr. David Hafler’s team at Yale University, in New Haven, Connecticut, dissects the role of our diet in the etiology of multiple sclerosis (MS).

 

In their study published in the scientific journal Nature Genetics, Mahdi’s group carried out a population study based on three RA cohorts from the UK and Sweden. Comparing RA patients and healthy individuals, they identified that smoking contributes to RA development by increasing an individual’s immune response to the self-antigen citrullinated α-enolase. Importantly, the association that they found between smoking and RA requires a susceptible genetic background (e.g. HLA-DRB1*0401, HLA-DRB1*0404). This means that smoking alone cannot cause RA in a person that does not have the “right” genes.

 

The increasingly high salt content of Western diets led Dr. Hafler’s group to investigate the effect of these recent dietary changes on autoimmunity. In their study published in the journal Nature, they observed that a high sodium chloride diet results in a high concentration of this mineral in organs. In turn, this results in an increased number of activated CD4+ T cells – a subset of immune cells that participate in the adaptive immune response – that become helper T 17 cells (Th17 cells). These Th17 cells are responsible for inflammatory conditions that promote MS as shown in mouse models of the disease. Thus high salt intake primes the immune system to respond to self-antigens in the context of MS.

 

Despite great advances in our understanding of the mechanisms through which environmental factors contribute to the development of autoimmune diseases, challenges remain. A given environmental factor does not affect the development of all autoimmune diseases in the same way. Smoking may increase the risk of RA onset in patients with genetic predispositions. However, nicotine is also known to alleviate symptoms of ulcerative colitis, a type of inflammatory bowel disease (IBD) closely related to the autoimmune condition Crohn’s disease. Overall, the fact remains that the incidence of autoimmune diseases has increased greatly in the last half century. And, to some extent, it seems that we are doing it to ourselves…


Crafty Pathogens Share the Cost of Resistance

 

By Elizabeth Ohneck, PhD

 

Bacteria have been evolving with us humans since we first came into being. Some of these microorganisms have become our indispensable partners, aiding our digestion, helping the development of our immune systems, and protecting us from less friendly bacteria. Others, in this less-friendly category, cause a vast number of illnesses and diseases, and have evolved to more insidious organisms, developing ways to outsmart our immune systems and resist antibiotics to survive within us and spread to new hosts. Pathogens like Neisseria gonorrhoeae, Staphylococcus aureus, and other multi-drug resistant “superbugs” have been continuously acquiring clever adaptations to protect themselves from our immune and antibiotic arsenals, leaving few options for patient treatment.

 

Many of the mutations that protect pathogenic bacteria from antimicrobial factors, however, come at a cost. Most antibiotics target cellular parts and processes essential to bacterial survival. To block antibiotic recognition of or action on these targets, bacteria must mutate critical cell components, which can reduce fitness, or the ability to grow and reproduce efficiently. Such fitness costs cause these mutants to grow more slowly than their wild-type, or “normal,” counterparts and other microorganisms present in the environment; thus, it is possible these mutants may not persist, as they might lose the battle for space and resources to their more fit opponents. In addition, some of these mutations decrease the ability of bacteria to produce virulence factors, which are critical in causing disease. Yet bacteria with mutations in important cell components are frequently recovered from patients with serious illness. How are these mutants able to successfully survive within the human host and cause severe disease?

 

A team from Vanderbilt University sought to answer this question with research published in Cell Host and Microbe in October. Hammer et al. examined Staphylococcus aureus small colony varients (SCVs), which are often isolated from patients with chronic disease and are resistant to multiple antibiotics. SCVs contain mutations in important biosynthetic pathways, resulting in slow growth and limited virulence factor production. Hammer et al. chose two primary mutants for their study: one unable to produce heme, and one unable to produce menaquinone, both of which are essential metabolites for bacterial respiration. Both mutants showed reduced growth rate and decreased ability to cause bone destruction in a mouse model of osteomyelitis. These defects were overcome by providing the metabolites during growth, demonstrating it is the inability of these mutants to produce the metabolites that causes their reduced fitness.

 

Interestingly, growing these two mutants together restored their growth and ability to cause bone destruction, suggesting the mutants could use the missing metabolite produced by the other mutant for normal growth and efficient virulence factor production. Surprisingly, growth of the mutant unable to produce menaquinone with another human pathogen, Enterococcus faecalis, also restored growth of the mutant, demonstrating that SCVs can use metabolites not only from other S. aureus, but from other bacterial species. Most importantly, the researchers demonstrated that these interactions can occur in patients during infection. The team isolated bacteria from the upper respiratory tract of patients with cystic fibrosis and found several bacterial species, including Staphylococcus epidermidis and Streptococcal species, that enhanced growth of the SCV mutants unable to produce heme, menaquinone, or both. In addition, they found many distinct SCVs that could rescue the growth of the heme and menaquinone mutants, as well as one another. These findings provide evidence that antibiotic resistant mutants can survive and cause disease despite fitness defects by borrowing factors important for growth from the surrounding microbial community, including the “friendly” bacteria that normally reside with in us, turning friends into foes.

 

It’s important to note that slow growth is an important factor in the antibiotic resistance of SCVs. When the heme or menaquinone synthesis mutants were rescued by growth with other strains, they became more sensitive to the antibiotic gentamicin, clearly demonstrating the trade-off between fitness and resistance. It’s plausible that wild-type S. aureus and SCVs work together for efficient, resistant infection. Wild-type strains can establish infection and increase the overall population, while the development of SCVs ensures population survival in the face of antibiotic treatment. The ability to use metabolites from other microorganisms is a clever evolutionary adaptation to compensate for the sacrifice in fitness made for the gain of antibiotic resistance, and an important consideration in the treatment of patients with bacterial infections and the development of new drugs.


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.


Can panic speed up the discovery of Ebola therapies?

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.