TAG: "Vaccines"

Study explains how early childhood vaccination reduces leukemia risk


Chronic infections push ‘pre-leukemia’ cells, common in newborns, into malignancy.

By Juliana Bunim, UC San Francisco

A team led by UC San Francisco researchers has discovered how a commonly administered vaccine protects against acute lymphoblastic leukemia (ALL), the most common type of childhood cancer.

The Haemophilus influenzae Type b (Hib) vaccine not only prevents ear infections and meningitis caused by the Hib bacterium, but also protects against ALL, which accounts for approximately 25 percent of cancer diagnoses among children younger than 15 years, according to the National Cancer Society. The Hib vaccine is part of the standard vaccination schedule recommended by the Centers for Disease Control and is routinely given to children in four doses before 15 months of age.

Though the cancer protection offered by the Hib vaccine has been well established in epidemiological studies, it is not well-known among the public at large, and the mechanism underlying this effect has been poorly understood. Now, in work to be reported on today (May 18) in Nature Immunology, an international team led by UCSF researchers has shown that recurrent Hib infections can put certain immune-system genes into overdrive, converting “pre-leukemia” blood cells — which are present in a surprisingly large number of newborns — into full-blown cancer.

“These experiments help explain why the incidence of leukemia has been dramatically reduced since the advent of regular vaccinations during infancy,” said Markus Müschen, M.D., Ph.D., professor of laboratory medicine at UCSF and senior author of the study. “Hib and other childhood infections can cause recurrent and vehement immune responses, which we have found could lead to leukemia, but infants that have received vaccines are largely protected and acquire long-term immunity through very mild immune reactions.”

Many newborns carry oncogenes — genes that could potentially cause cancer — in their blood cells, but only 1 in 10,000 will eventually develop ALL. In the new study, the researchers tested the idea that chronic inflammation caused by recurrent infections might cause “collateral damage” — additional genetic lesions — in blood cells already carrying an oncogene,  promoting their transformation to overt disease.

Led by co-first authors Srividya Swaminathan, Ph.D., a former UCSF postdoctoral fellow now at Stanford University School of Medicine, and Lars Klemm, assistant research specialist at UCSF, the research team conducted experiments with mice that homed in on two enzymes known as AID and RAG as the drivers of this process.

AID and RAG introduce mutations in DNA that allow immune cells to adapt to infectious challenges, and these enzymes are necessary for a normal and efficient immune response. But in the presence of chronic infection, the group found, AID and RAG are strongly hyperactivated, and they cut and mutate genes randomly, including important gatekeepers against cancer.

By studying genetically engineered pre-leukemia cells lacking either AID or RAG, as well as cells lacking both enzymes, the team found that AID and RAG working together is critical to introduce the additional lesions that result in life-threatening disease.

Though the researchers focused on Hib, a bacterial infection, they believe that the same mechanisms may be at work in viral infections. The team is currently conducting experiments to determine if protection against leukemia is also provided by vaccines against viral infections, such as the well known MMR vaccine at the center of recent anti-vaccination controversies.

Mel F. Greaves, M.D., Ph.D., professor of cell biology at the Institute of Cancer Research, in London, is among the scientists who developed the theory that chronic and recurrent immune reactions during infancy promote cancer in children and one of the co-authors of the study. “The study provides mechanistic support for the hypothesis that infection or inflammation promotes the evolution of childhood leukemia and that the timing of common infections in early life is critical,” said Greaves.

Also participating in the research were scientists from the University of Freiburg; Cambridge University; the Wellcome Trust Sanger Institute; the University of Southern California; Heinrich-Heine-Universität Düsseldorf; the University of Ulm; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Yale School of Medicine.

The work was funded by the National Institutes of Health; the National Cancer Institute; the Leukemia and Lymphoma Society; the William Lawrence and Blanche Hughes Foundation; the California Institute for Regenerative Medicine; the Wellcome Trust; and Cancer Research UK.

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Persistence yields progress in AIDS vaccine research at UC Santa Cruz


Phil Berman developing new approach based on old vaccine, advances in HIV immunology.

Veteran vaccine researcher Phil Berman is the Baskin Professor of Biomolecular Engineering at UC Santa Cruz. (Photo by C. Lagattuta, UC Santa Cruz)

By Tim Stephens, UC Santa Cruz

Phil Berman has been working to develop an AIDS vaccine for nearly 30 years, first at the pioneering biotech company Genentech, then as co-founder of VaxGen, and now at UC Santa Cruz, where he is the Baskin Professor of Biomolecular Engineering. Since his arrival at UC Santa Cruz in 2006, Berman has established a major vaccine research effort funded by a series of grants from the National Institutes of Health, including two new grants in 2014 totaling $2.6 million.

The latest results from this effort have Berman sounding optimistic about the prospects for a vaccine that can be effective in protecting against HIV infection. His lab has developed new vaccine candidates that he said are promising enough to consider advancing into clinical trials within the next two years.

Berman has redesigned a vaccine that he invented while at Genentech and led through clinical testing at VaxGen. This earlier vaccine, called AIDSVAX, was used in combination with another experimental vaccine in a large-scale clinical trial in Thailand involving 16,000 people. This trial (known as RV 144) showed that the combined vaccine was safe and 31 percent effective in preventing new HIV infections.

Protective effect

After the results of the trial were released in 2009, Berman and other researchers pored over them to understand the nature of the protective effect. Although the effect was small, RV 144 is still the only clinical trial in which a vaccine has shown any protective effect at all against HIV infection.

“By analyzing the results from RV 144, we started to understand the response to the vaccine, and I developed some new ideas for how to improve it,” Berman said. “By building on an existing vaccine concept, rather than developing a new one from scratch, we can save millions of dollars and years of time getting the new vaccine into the clinic.”

Researchers believe that for an AIDS vaccine to be effective, it must stimulate the immune system to make “broadly neutralizing antibodies” that are effective against multiple strains of the virus. HIV is so highly mutable that replication of the virus in an infected person gives rise to a genetically diverse population of circulating virus, and this variability helps the virus evade detection and neutralization by the immune system.

A neutralizing antibody recognizes a foreign protein (called an antigen), and by binding to it is able to block or neutralize the infectivity of the virus. For example, neutralizing antibodies that target an HIV envelope protein called gp120 can block a crucial part of the infection process in which gp120 binds to a receptor on the surface of T cells. The AIDSVAX vaccine was based on the gp120 envelope protein.

Elite neutralizers

One key to improving the vaccine, Berman said, came from independent lines of investigation pointing to the importance of antibodies that recognize a specific segment of gp120 known as the V1/V2 domain. The RV 144 trial results showed that protection was correlated with antibodies to this domain. Meanwhile, broadly neutralizing antibodies to this domain were isolated from a rare group of people known as “elite neutralizers,” who produce antibodies that potently neutralize multiple strains of the virus.

Studies of these broadly neutralizing antibodies yielded another crucial finding. The part of an antigen that is recognized by an antibody is called an epitope, and it is usually a specific sequence of amino acids in the antigen protein. Scientists studying antibodies from elite neutralizers, however, discovered that many of the most potent neutralizing antibodies actually recognize carbohydrate components called glycans that are attached to the gp120 envelope protein.

“We knew that these broadly neutralizing antibodies existed for many years, but it came as a great surprise that they were directed to carbohydrate epitopes rather than the more common amino acid epitopes,” Berman said. “We found that the vaccine that gave partial protection in the RV 144 trial had very little of the kind of carbohydrate required to bind these antibodies.”

So Berman’s lab set out to produce antigens that would induce a strong antibody response to the glycan-dependent epitopes in the V1/V2 domain. Attaching the right kind of glycans to the protein was just one of the challenges. The envelope protein has dozens of epitopes, and most of the immune response is directed at ones that don’t induce neutralizing antibodies. Compared to these so-called “decoy epitopes,” the glycan-dependent epitopes are only weakly immunogenic. Berman decided to use fragments of gp120 to make protein scaffolds that would present to the immune system only the glycan-dependent epitopes recognized by broadly neutralizing antibodies, while eliminating the other gp120 epitopes.

“The trick is to make the scaffolds fold up into the right three-dimensional shape, as well as incorporating the right glycans,” he said.

Immunogenicity studies

Berman’s lab is now developing cell lines genetically engineered to produce viral proteins with the right structure and glycan epitopes to bind to broadly neutralizing antibodies with high affinity. This strong binding suggests that vaccination with these antigens could stimulate the immune system to produce the broadly neutralizing antibodies. In a paper published last year in the Journal of Biological Chemistry, Berman’s team described the results of immunogenicity studies of these antigens.

“I think we’ve got candidates that should be seriously considered for advancement to clinical testing,” Berman said. “We started with a molecule that has already been tested in humans, and we’ve rebuilt it using envelope proteins and scaffolds with the right carbohydrates.”

Berman’s lab is continuing to generate and screen new cell lines, looking for those that give the most consistent and reproducible production of antigens that perform well in immunogenicity studies. Thanks to NIH funding, he now has the facilities and specialized equipment to conduct rapid screening of cell lines and produce large quantities of proteins for vaccine research.

Berman is also training the researchers and graduate and undergraduate students in his lab in the demanding techniques needed to develop this kind of recombinant vaccine. He noted that plans to repeat the RV 144 trial were stymied by the inability of other labs to reproduce the AIDSVAX vaccine, since VaxGen was no longer in operation. Similarly, he said, efforts to make Ebola antigens for a potential vaccine during the current outbreak in West Africa have been slowed by a shortage of researchers trained in these techniques.

“We’re training people with the skills needed to respond to emerging diseases like Ebola,” Berman said.

Berman’s research is supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute on Drug Abuse (NIDA).

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Vaccine field trials for deadly ‘foothill abortion’ cattle disease expanding


Ranchers a step closer to having vaccine available to treat disease that kills cow fetuses.

A new vaccine developed by veterinary immunologist Jeff Stott shows promise for preventing foothill abortion disease, which kills calves before or at birth. (Photo by Don Preisler, UC Davis School of Veterinary Medicine)

By Pat Bailey and Monique Garcia Gunther, UC Davis

Thanks in part to researchers at the UC Davis School of Veterinary Medicine, cattle ranchers in California, Nevada and Oregon are one step closer to having a vaccine available to treat a tick-borne bacterial disease — commonly known as foothill abortion — which kills cow fetuses.

The U.S. Department of Agriculture approved the expansion of ongoing field trials in November for an experimental vaccine, developed by UC Davis veterinary researchers, after it was shown to be effective in preventing foothill abortion in more than 2,000 cattle. The expanded trials began in April and will further establish the vaccine’s effectiveness in varied conditions as well as provide relief to ranchers. (A news article about the vaccine trials will appear May 8 in the journal Science.)

Cattle ranchers seek relief

Foothill abortion — endemic in California’s coastal range and the foothill regions of California, Southern Oregon and Northern Nevada — is a bacterial disease in cattle also known as epizootic bovine abortion. It is a major cause of economic loss for California beef producers, annually causing the death of an estimated 45,000 to 90,000 calves.

The disease is transmitted by bites from the pajaroello tick, found only in the intermountain West. The tick lives in the soil around juniper, pine and oak trees, and in dry brush areas and around rock outcroppings of foothill rangelands. The disease became known as “foothill abortion” after ranchers in the 1930s and 1940s noticed that the pregnant heifers they sent to pasture in the foothills aborted after returning to valley pastures. Infected pregnant cows show no obvious symptoms but the bacteria can infect their fetuses in the first half of gestation before they develop an immune system capable of fighting off the infection. Cows will carry the infected fetus to term but the calves are born either dead or very weak and fail to thrive.

“Our Western cattle producers are desperate for some relief to stop their losses resulting from this disease,” said professor Jeff Stott, a UC Davis veterinary immunologist. Stott has led the effort in collaboration with the California Cattlemen’s Association, the USDA Center for Veterinary Biologics, the Animal Health Branch of the California Department of Food and Agriculture, the Nevada Department of Agriculture, and the University of Nevada, Reno.

Fifth-generation rancher Buck Parks from Lassen County is one example of a cattle producer who has experienced losses as a result of foothill abortion. His family first started noticing aborted cow fetuses in the late 1950s, but couldn’t pin down a cause. Until recently, he was losing an average of 25-35 calves each year to the disease from a herd of about 300 cows. He said about 20 percent of the losses are from “first-calf heifers,” or first-time mother cows. According to Parks, while the disease is regional, and spotty within those regions, it is challenging to run a cattle ranch for those affected.

“For those of us who suffer, it’s a very difficult thing to deal with,” he said. “Like any business, these kinds of losses make it tough to operate within our margins.”

Parks has been participating in the trials since the experimental vaccine first became available four years ago and has experienced significant results.

“Let’s just say that this year we only saw eight abortions,” he said.

Stott is confident the vaccine can help prevent foothill abortion for cattle producers like Parks. There already has been interest from niche pharmaceutical companies in manufacturing the vaccine.

Quest for elusive vaccine

Identifying the cause of foothill abortion and developing a vaccine to prevent it has proved a long-term challenge for researchers at the UC Davis School of Veterinary Medicine. In fact, some scientists have spent entire careers pursuing identification of the causative agent of foothill abortion.

In the 1970s, UC Davis veterinary scientists determined that the pajaroello tick transmitted the disease and in the early 1980s found evidence that infected cow fetuses were producing an immune response to an unidentified microbe.

Progress was slow due to the inability to culture the microbe in the laboratory, and it wasn’t until the beginning of the new millennium when UC Davis researchers managed to identify a causative agent using molecular biology tools.

In 2000, Stott and colleagues made what they considered to be a dramatic breakthrough in vaccine development when they discovered how to grow the live bacteria in mice lacking an immune system. This led them to initiate studies to develop an experimental live-bacteria-based vaccine in 2009 in collaboration with the University of Nevada, Reno.

Preliminary vaccine field trials began in 2011 and have since involved more than 4,000 cattle in California and Nevada. The expanded trials involving several thousand more cattle are expected to last into 2017.

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Malaria vaccine candidate produced from algae


Cheap, green technique advances efforts toward malaria transmission vaccine in humans.

Algae technique used to produce candidate vaccine that prevents transmission of the malaria parasite from host to mosquito.

By Heather Buschman, UC San Diego

Researchers at the UC San Diego School of Medicine used algae as a mini-factory to produce a malaria parasite protein. The algae-produced protein, paired with an immune-boosting cocktail suitable for use in humans, generated antibodies in mice that nearly eliminated mosquito infection by the malaria parasite. The method, published Feb. 17 by Infection and Immunity, is the newest attempt to develop a vaccine that prevents transmission of the malaria parasite from host to mosquito.

“Most malaria vaccine approaches are aimed at preventing humans from becoming infected when bitten by mosquitos that carry the parasite,” said Joseph M. Vinetz, M.D., professor of medicine and senior author of the study. “Our approach is to prevent transmission of the malaria parasite from infected humans to mosquitoes. This approach is similar to that of the current measles vaccine, which is such a hot topic of discussion these days, because the goal is to generate herd immunity in a population. We think that this approach is key to global malaria elimination, too.”

To do this, Vinetz and team wanted to produce a large quantity of properly folded Pfs25, a protein found on the surface of the malaria parasite’s reproductive cells, which are only present within the mosquito’s gut after it feeds on a malaria-infected blood meal. Since antibodies against Pfs25 can halt the parasite’s lifecycle in the mosquito, they might also block transmission of the parasite to the next host.

However, properly folded Pfs25 that induces transmission-blocking antibodies has been difficult to produce in the lab. To overcome this problem, researchers turned to an algae better known for its ability to produce sustainable biofuels. They introduced the Pfs25 gene into the algae by shooting the DNA into the plant cell’s nucleus. Then, after they let the algae do the work of replicating, building and folding the protein, the team was able to purify enough functional Pfs25 for laboratory testing.

Besides its effectiveness as a protein producer, algae is an advantageous tool for developing vaccines because it’s cheap, easy and environmentally friendly. The only requirement is simple chemical nutrients to feed the algae, which can be grown in plastic bags and easily scaled up to produce large quantities of desired proteins.

Vinetz and collaborators at the Infectious Disease Research Institute in Seattle also tested several new adjuvants, molecules that help stimulate the immune system’s response to Pfs25. The best Pfs25/adjuvant combination elicited a uniquely robust antibody response in mice with high affinity and avidity — antibodies that specifically and strongly reacted with the malaria parasite’s reproductive cells.

Mosquitos were fed malaria parasites in the presence of control serum or immune serum collected from mice vaccinated with algae-produced Pfs25 in the presence of the new adjuvant. Eight days later, the researchers examined the mosquitos’ guts for the presence of the malaria parasite.

The results were dramatic: only one of 24 mosquitos (4.2 percent) that consumed the Pfs25/adjuvant-treated mouse serum was positive for the malaria parasite. That’s compared to the 28 infected mosquitoes out of the 40 in the control group (70 percent).

“We are really excited to see that Pfs25 produced by algae can effectively prevent malaria parasites from developing within the mosquito,” said study co-author Stephen P. Mayfield, Ph.D., professor of biological sciences and director of the California Center for Algae Biotechnology at UC San Diego. “With the low cost of algal production, this may be the only system that can make an economic malaria vaccine. Now we’re looking forward to comparing algae-produced Pfs25 and adjuvant head-to-head against other approaches to malaria vaccine production and administration.”

Malaria is the leading cause of death and disease in many developing countries. In 2012, there were approximately 207 million cases of malaria infection worldwide. Young children and pregnant women are most affected by the disease.

Co-authors of this study also include Kailash P. Patra, Fengwu Li, Sheyenne Baga, UC San Diego; Darrick Carter, Steven G. Reed, Infectious Disease Research Institute; and James A. Gregory, formerly at UC San Diego Division of Biological Sciences, currently at Icahn School of Medicine at Mount Sinai.

This research was funded, in part, by the National Institutes of Health (grants U19AI089681, 1R01AI067727, K24AI068903, D43TW007120 and P30NS047101), U.S. Public Health Service, U.S. Department of Energy, San Diego Foundation, California Energy Commission and Bill and Melinda Gates Foundation.

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UC plans to require vaccinations for incoming students


The plan is being phased in over three years.

Credit: iStock

By Alec Rosenberg

The University of California will require incoming students to be screened for tuberculosis and vaccinated for measles, mumps, rubella, chicken pox, meningococcus, tetanus and whooping cough, under a plan set to take effect in 2017.

Currently, the UC system only requires students to be vaccinated against hepatitis B, though several campuses have additional requirements.

The plan — designed to help protect the health of students and campus communities — has been in the works for a year. But the need is more pressing than ever, given the current multistate measles outbreak and the re-emergence of other vaccine-preventable diseases among those not completely immunized.

“I’m really excited that there’s support and momentum for this new immunization plan,” said Dr. Gina Fleming, medical director for the UC Student Health Insurance Plan. “We know that these preventive measures are effective.”

Three-year phase-in

The plan is being phased in over three years. The first phase focuses on building awareness among students about the upcoming requirement, with all fall 2015 incoming UC students receiving notification of the recommended vaccines and the process for making them mandatory. The intent of the plan is to set a baseline for all of UC, but does not prevent individual campuses from setting immunization standards for all students, or implementing the plan more rapidly.

It was developed based on recommendations from the California Department of Public Health, and in consultation with UC’s student health center directors, vice chancellors for student affairs and the UC system senior vice president for health sciences and services.

It will require that by 2017 all incoming students show documentation not only for hepatitis B vaccination but also for TB screening and four more vaccines: measles, mumps and rubella; meningococcus; varicella (chicken pox); and tetanus, diphtheria and pertussis (whooping cough).

“The University of California is committed to protecting the health and well-being of our students,” said Mary Knudtson, executive director of the UC Santa Cruz Student Health Center and chair of the UC Immunization Policy Committee. “Therefore, all of the UC campuses are implementing procedures to ensure that students are educated about, and receive, vaccinations to prevent potentially dangerous illnesses and undergo screening to identify those who may have infectious tuberculosis.”

Starting in fall 2016, all incoming UC students will be expected to have their required vaccines and enter the data into the university’s electronic medical record platform. But the plan is not to enforce the requirement until the following year. Starting in fall 2017, UC students who do not meet the vaccination requirement will have a hold put on their registration. The rationale for the phased approach is to ensure that the process runs smoothly before potentially impacting students’ ability to register for classes.

All UC campuses have experienced cases of vaccine-preventable diseases in recent years — something not unique among college campuses, which have varying vaccination requirements. For example, only about half of states have laws requiring all college students to be vaccinated against measles, according to a U.S. Centers for Disease Control and Prevention database.

“Despite the fact that many people receive the recommended vaccines, there are still documented cases of outbreaks of vaccine-preventable diseases in California and on the campuses each year amongst those who were not properly immunized,” Knudtson said. “All students are strongly encouraged to obtain the vaccines recommended by the California Department of Public Health prior to starting classes.”

Breaking down barriers

While getting such vaccines has long been considered a good public health practice, the cost of vaccines and the difficulty for student health staff to obtain and verify the information have been barriers to implementation.

Two developments have broken down those barriers, Fleming said. Now that the Affordable Care Act provides insurance coverage for vaccines, the cost of vaccination is less of a problem. Also, a new electronic medical record platform soon will allow UC students to directly enter their vaccination date. Four campuses will be piloting the module for entering vaccination data this fall, and the remaining campuses anticipate being able to use it by fall 2016.

The issue of immunization has evolved into a hot topic of discussion in California and across the nation in recent weeks after a measles outbreak that started at Disneyland. On Wednesday, state Senators Richard Pan and Ben Allen announced they will introduce legislation that would eliminate the ability for parents of school children to opt out of vaccinating their kids based on a personal belief.

UC’s plan will allow exemptions for medical or religious purposes, Fleming said. In the coming months, officials will discuss how to handle requests for other exemptions and how to validate the vaccination information.

“We need to be mindful of the population we’re serving,” Fleming said.

UC’s plan might be extended to already enrolled students and additional vaccines could be added later, such as meningococcus B, Fleming said. Vaccines recommended for preventive care include vaccines for hepatitis A, HPV, influenza, polio and pneumococcal pneumonia.

Officials are determining whether additional approvals are needed to adopt the plan, Fleming said, even as they move forward with implementation.

Meanwhile, leadership in student affairs and student health centers are working with other campus departments to inform students about the plan.

“That’s really a critical piece,” Fleming said. “We can’t expect students to adhere to a requirement that they haven’t heard about. They need to know what the plan is.”

Related link:
Associated Press: Los Alamos National Lab creates website for measles fight

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Project uses tech to help boost vaccination rates in India


UC Berkeley students turn to crowdfunding to support further software development.

Emmunify co-founder Anandamoy Sen, now a UC Berkeley alumnus, holds a prototype of the portable record system. The chip, which contains vaccine records, is attached to a cell phone, ready to be synced to a health care worker’s mobile device. (Photo courtesy of Julia Walsh)

By Sarah Yang,  UC Berkeley

UC Berkeley students are creating a new tool that could soon make it far easier for children in developing nations to get life-saving vaccines.

As part of a project called Emmunify, the students simplify medical record-keeping by storing patient vaccination records on a portable chip that can then be accessed by a health care provider without the need for Internet access.

“Electronic health records are not new, but in developed nations, there is more IT infrastructure in place that allows some health providers and patients to have access to medical data,” says project team member Jennifer Sisto, a graduate student in public health. “We wanted something that would be effective in areas with limited healthcare data and IT resources, so we focused on providing crucial information, not setting up an entire electronic health record system.”

Emmunify was the brainchild of three Berkeley MBA students, who entered the project in the campus’s 2012 Hacking Health competition for the most innovative ideas in digital health. The project emerged as the grand prize winner, earning $2,000 in seed money to help build a better prototype and conduct feasibility testing.

With the leadership of faculty adviser Dr. Julia Walsh, adjunct professor of maternal and child health, the team connected with nonprofit health providers in India and began preparing to pilot-test the technology in New Delhi, where under half the children are fully immunized.

Rather than attempt to include a patient’s entire medical history on this chip, the Emmunify team kept the data focused on vaccination history.

“We know that raising vaccination rates among children raises school attendance, improves cognitive abilities, decreases malnutrition and increases earning power as adults,” says Walsh. “This is a simple tool to help get kids out of poverty.”

The Emmunify chip is attached to a user’s cell phone, and data is transferred to the health provider’s phone, tablet or other computer through near-field communication, a feature that is increasingly common in today’s mobile devices. A free app must be downloaded so the device can read the data on the chip. The researchers note that most families have access to at least one cell phone, and that the system is designed to be operable on various platforms.

“In many cases, families have to go to six different places at different times to get vaccinations for their children, and they are expected to keep the records on a form or other piece of paper that easily gets lost,” says Walsh. “This tool solves that problem by keeping the data on a phone and in an easily readable format.”

Emmunify could also be used to help direct resources where they are needed. Communities can track how many vaccines have been delivered and used, and health administrators will know when supplies are low and more vaccines are needed.

Ultimately, the system could help increase vaccination rates by sending patients automated voicemail reminders in their local language to remind them when their next shot is due.

“There is a lot of evidence from epidemiological studies that when it comes to basic healthcare, it’s not the new flashy gizmos that are important,” says Sisto. “We just want something basic that works. The tool can be really simple.”

The current team consists of two Berkeley alumni, including co-founder Anandamoy Sen, and six undergraduate and graduate students from Berkeley’s Department of Electrical Engineering and Computer Sciences and the School of Public Health.

Since Emmunify’s debut in 2012, the researchers have won additional funding through other contests, including Big Ideas@Berkeley, which is supported by several campus centers and institutes. This year, Big Ideas partnered with Indiegogo, a crowdfunding site, to help raise money for winning projects.

The Emmunify team hopes to raise $25,000 to support further software development and to deploy the technology in New Delhi.

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Biochemists build largest synthetic molecular ‘cage’ ever


New nanoscale protein container could lead to synthetic vaccines.

Todd Yeates and Yen-Ting Lai, UCLA

UCLA biochemists have created the largest-ever protein that self-assembles into a molecular “cage.” The research could lead to synthetic vaccines that protect people from the flu, HIV and other diseases.

At a size hundreds of times smaller than a human cell, it also could lead to new methods of delivering pharmaceuticals inside of cells, or to the creation of new nanoscale materials.

The protein assembly, which is shaped like a cube, was constructed from 24 copies of a protein designed in the laboratory of Todd Yeates, a UCLA professor of chemistry and biochemistry. It is porous — more so than any other protein assembly ever created — with large openings that would enable other large protein molecules to enter and exit.

The research was recently published online in the journal Nature Chemistry and will appear in a future print edition.

Yeates, the study’s senior author, has sought to build complex protein structures that self-assemble since he first published research on self-assembling proteins in 2001. In 2012, he and colleagues produced a self-assembling molecular cage made from 12 protein pieces combined perfectly like pieces of a puzzle. Now they have done so with 24 pieces, and they are currently attempting to design a molecular cage with 60 pieces. Building each larger protein presented new scientific challenges, but the bigger sizes could potentially carry more “cargo.”

In principle, these molecular structures should be able to carry cargo that could then be released inside of cells, said Yeates, who is a member of the UCLA–Department of Energy Institute of Genomics and Proteomics and the California NanoSystems Institute at UCLA.

Yeates’ research was funded by the National Science Foundation and the UCLA–DOE Institute of Genomics and Proteomics. The lead author was Yen-Ting Lai, who conducted the research as a UCLA graduate student in Yeates’ laboratory and is now a postdoctoral scholar at Arizona State University.

The molecular cube is probably too porous to serve as a container — for medicine, for example — inside a human body. “But the design principles for making a cage that is more closed would be the same,” Yeates said, adding that there are ways to make the cage less stable when it gets into a cell, so that it would release its cargo, such as a toxin that could kill a cancer cell.

Yeates said that his lab’s method also could lead to the production of synthetic vaccines that would mimic what a cell sees when it’s infected by a virus. The vaccines would provoke a strong response from the body’s immune system and perhaps provide better protection from diseases than traditional vaccines.

Yeates has started a research collaboration with Peter Kwong, chief of the structural biology section at the National Institutes of Health and a national leader in the structural biology of disease viruses. They will conduct research on attaching viral antigens to molecular cages.

Other co-authors of the Nature Chemistry research were Carol Robinson, Eamonn Reading and Arthur Laganowsky of the University of Oxford; Francisco Asturias and Kuang-Lei Tsai of the Scripps Research Institute; and John Tainer and Greg Hura of the Lawrence Berkeley National Laboratory.

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Building molecular ‘cages’ to fight disease

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Ebola genome browser now online


UC Santa Cruz Genomics Institute releases bioinformatic tool to assist vaccine efforts.

Jim Kent, UC Santa Cruz

The UC Santa Cruz Genomics Institute late Tuesday (Sept. 30) released a new Ebola genome browser to assist global efforts to develop a vaccine and antiserum to help stop the spread of the Ebola virus.

The team, led by UC Santa Cruz researcher Jim Kent, worked around the clock for the past week, communicating with international partners to gather and present the most current data. The Ebola virus browser aligns five strains of Ebola with two strains of the related Marburg virus. Within these strains, Kent and other members of the UC Santa Cruz Genome Browser team have aligned 148 individual viral genomes, including 102 from the current West Africa outbreak.

UC Santa Cruz has established the UCSC Ebola Genome Portal, with links to the new Ebola genome browser as well as links to all the relevant scientific literature on the virus.

“Ebola has been one of my biggest fears ever since I learned about it in my first microbiology class in 1997,” said Kent, who 14 years ago created the first working draft of the human genome.  “We need a heroic worldwide effort to contain Ebola. Making an informatics resource like the genome browser for Ebola researchers is the least we could do.”

Scientists around the world can access the open-source browser to compare genetic changes in the virus genome and areas where it remains the same. The browser allows scientists and researchers from drug companies, other universities, and governments to study the virus and its genomic changes as they seek a solution to halt the epidemic.

The release of the new Ebola genome browser comes as the U.S. Centers for Disease Control and Prevention Tuesday confirmed the first case of Ebola in the United States.

The Ebola browser was started shortly after a phone conversation between Kent and his sister, an epidemiologist at the CDC, who spoke of how she and her staff were consumed with Ebola research in the face of the escalating crisis. UC Santa Cruz professor Phil Berman, an HIV specialist, had also asked Kent for help with his efforts in developing a vaccine for Ebola.

Kent asked his supervisor, UC Santa Cruz bioinformatics researcher David Haussler, if he could divert his team to Ebola work.  Haussler replied with an enthusiastic affirmative, and they pulled together a team of UC Santa Cruz bioinformatics scientists that, within a week, was able to create a fully functional Ebola genome browser.

“The incredible speed with which this group was able to assemble all the genetic information about Ebola and make it available to the world shows what a great team Jim Kent has assembled,” Haussler said.

In June 2000, Kent and Haussler released the first working draft of the human genome sequence on the Web. Two months later, Kent developed the UCSC Genome Browser, which has become an essential resource to biomedical science.

In a similar marshaling of forces in the face of a worldwide threat 11 years ago, UC Santa Cruz researchers created a SARS virus browser.

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New vaccine may be stronger weapon against both TB and leprosy


Research finds variant of existing vaccine offers stronger protection against both diseases.

Antigen 85B structure

In many parts of the world, leprosy and tuberculosis live side-by-side. Worldwide there are approximately 233,000 new cases of leprosy per year, with nearly all of them occurring where tuberculosis is endemic.

The currently available century-old vaccine Bacille Calmette-Guerin, or BCG, provides only partial protection against both tuberculosis and leprosy, so a more potent vaccine is needed to combat both diseases. UCLA-led research may have found a stronger weapon against both diseases.

In a study published in the September issue of the peer-reviewed journal Infection and Immunity, the researchers found that rBCG30, a recombinant variant of BCG that overexpresses a highly abundant 30 kDa protein of the tuberculosis bacterium known as Antigen 85B, is superior to BCG in protecting against tuberculosis in animal models, and also cross protects against leprosy. In addition, they found that boosting rBCG30 with the Antigen 85B protein, a protein also expressed by the leprosy bacillus, provides considerably stronger protection against leprosy.

“This is the first study demonstrating that an improved vaccine against tuberculosis also offers cross-protection against Mycobacterium leprae, the causative agent of leprosy,” said Dr. Marcus A. Horwitz, professor of medicine and microbiology, immunology and molecular genetics, and the study’s senior author. “That means that this vaccine has promise for better protecting against both major diseases at the same time.

“It is also the first study demonstrating that boosting a recombinant BCG vaccine further improves cross-protection against leprosy,” he added.

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A key step toward a safer strep vaccine


UC San Diego gene discovery identifies molecular pathway to potential preventive treatment.

Electron micrograph, false color, of group A Streptococcus bacteria

An international team of scientists, led by researchers at the UC San Diego School of Medicine, have identified the genes encoding a molecule that famously defines Group A Streptococcus (strep), a pathogenic bacterial species responsible for more than 700 million infections worldwide each year.

The findings, published online in today’s (June 11) issue of Cell Host & Microbe, shed new light on how strep bacteria resists the human immune system and provides a new strategy for developing a safe and broadly effective vaccine against strep throat, necrotizing fasciitis (flesh-eating disease) and rheumatic heart disease.

“Most people experience one or more painful strep throat infections as a child or young adult,” said senior author Victor Nizet, M.D., professor of pediatrics and pharmacy. “Developing a broadly effective and safe strep vaccine could prevent this suffering and reduce lost time and productivity at school and work, estimated to cost $2 billion annually.”

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Potential lung cancer vaccine shows renewed promise


Tecemotide a potential maintenance therapy to prolong survival, improve quality of life.

Michael DeGregorio, UC Davis

Researchers at UC Davis have found that the investigational cancer vaccine tecemotide, when administered with the chemotherapeutic cisplatin, boosted immune response and reduced the number of tumors in mice with lung cancer. The study also found that radiation treatments did not significantly impair the immune response. The paper was published on March 10 in the journal Cancer Immunology Research, an American Association for Cancer Research (AACR) publication.

Though tecemotide, also known as Stimuvax, has shown great potential at times, the recent Phase III trial found no overall survival benefit for patients with non-small cell lung cancer (NSCLC). However, further analysis showed one group of patients, who received concurrent chemotherapy and radiation followed by tecemotide, did benefit from the vaccine. As a result, tecemotide’s manufacturer, Merck KGaA, is sponsoring additional post-clinical animal and human studies, so far with good results.

“There aren’t any good options for patients with inoperable stage III lung cancer following mainline chemotherapies,” said UC Davis professor of medicine and lead author Michael DeGregorio. “We are looking at tecemotide as a potential maintenance therapy to prolong survival and improve quality of life.”

Tecemotide activates an immune response by targeting the protein MUC1, which is often overexpressed in lung, breast, prostate and other cancers. The vaccine stimulates production of interferon gamma and MUC1-targeted killer T-lymphocytes, which seek out and destroy MUC1 cancer cells.

The team, which included investigators from the UC Davis School of Veterinary Medicine and the Department of Radiation Oncology, wanted to know if cisplatin/tecemotide treatments, along with radiation therapy, could boost the immune response and alter lung cancer’s trajectory, stabilizing the disease.

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Jonas Salk’s personal papers going to UC San Diego Library


Physician developed the world’s first successful polio vaccine.

Jonas Salk (left) with an unidentified man in front of the Salk Institute, during construction.

The UC San Diego Library has become the official repository for the papers of Jonas Salk, noted physician, virologist and humanitarian, best known for his development of the world’s first successful vaccine for the prevention of polio.

The papers — which constitute almost 600 linear feet (or nearly 900 boxes) — were recently donated to the Library’s Mandeville Special Collections by Salk’s sons, Peter, Darrell and Jonathan, all of whom, like their father, trained as physicians and are involved in medical and scientific activities.

While recognized worldwide for his significant contributions, Jonas Salk is particularly noted locally for his founding of the Salk Institute for Biological Studies adjacent to UC San Diego and the impact this had on the city’s metamorphosis into a major center for biomedical and scientific research and discovery. The institute will celebrate the Jonas Salk Centenary in the fall of 2014 and, as part of this notable milestone, the library will hold a major exhibition of the Salk Papers and collaborate with the institute on other celebratory events.

“It is a great honor for the library to be the official repository for Jonas Salk’s papers,” said Brian E. C. Schottlaender, The Audrey Geisel University Librarian at UC San Diego. “The UC San Diego Library’s Mandeville Special Collections houses the papers of some of the world’s most prominent and accomplished scientists, including Francis Crick, Stanley Miller and Leo Szilard, as well as Nobel laureates Harold Urey, Hannes Alfven and Maria Goeppert Mayer. The papers of Jonas Salk are an excellent complement to these materials.”

The Salk papers constitute an exhaustive source of documentation on Salk’s professional and scientific activities. The papers cover the period from the mid-1940s to his death in 1995; best documented are activities largely related to the development of the Salk polio vaccine in the mid-1950s to the early 1960s and the founding of the Salk Institute. The papers cover general correspondence, files relating to polio, his writings, photographs, artifacts — including two dictating machines — personal writings and various research materials.

The collection includes correspondence with a number of prominent scientists and others, including Basil O’Connor and officers of the National Foundation for Infantile Paralysis/March of Dimes; immunologists Thomas Francis and Albert Sabin; physicist and biologist Leo Szilard; mathematician and philosopher Jacob Bronowski; architect Louis Kahn and other important figures in the worlds of art, science, education, public administration and humanitarianism.

Salk came to La Jolla following a career in clinical medicine and virology research. After obtaining his M.D. degree at the New York University School of Medicine in 1939, he served as a staff physician at Mount Sinai Hospital in New York City. He then joined his mentor, Dr. Thomas Francis, as a research fellow at the University of Michigan. There he worked to develop an influenza vaccine at the behest of the U.S. Army. In 1947, he was appointed director of the Virus Research Laboratory at the University of Pittsburgh School of Medicine, where he began to put together the techniques that would lead to his polio vaccine.

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