HPV vaccine can protect women across a broad age range

A research paper published in The Lancet Infectious Diseases reported that the human papillomavirus (HPV) vaccine is safe and efficacious across a wide age range of women. The international study found that it protects against HPV infection in women older than 26 years. Vaccination programs worldwide currently target routine vaccination of women 26 years and younger.

The study recruited women in 12 countries across four continents. Cosette Wheeler, PhD, at The University of New Mexico Comprehensive Cancer Center, was the lead author of the report.

The human papillomaviruses cause cancer of the cervix, anus, and middle throat. Five types of HPV account for about 85 percent of all invasive cervical cancer cases. HPV vaccines are expected to prevent most of these cancer cases.

Many countries routinely vaccinate girls and boys 25 years and younger, although vaccination rates in the United States remain low. In the US, only about 40 percent of girls and 21 percent of boys receive the three-dose vaccination series. The earlier the vaccine is given, the more efficacious it can be.

This study focused on the benefit of vaccinating women 26 years and older. Infection with HPV can take place at any time throughout adulthood and women in this age group may have already been exposed to HPV. The study showed that women in this age group were still protected from HPV infections.

The scientists followed each woman for four to seven years. They found that the vaccine protected the women against HPV infections during the follow-up period and that the women were protected from many types of HPV across a broad age range. These study results are essential to new approaches in cancer prevention, particularly those that are investigating combined approaches of cervical screening and vaccination in adult women.

Cosette Wheeler, PhD is a UNM Regents Professor in the Departments of Pathology and Obstetrics and Gynecology at the University of New Mexico Health Sciences Center. She holds the Victor and Ruby Hansen Surface Endowed Chair in Translational Medicine and Public Health. Her New Mexico research group has contributed for over 20 years to understanding the molecular epidemiology of human papillomaviruses (HPV) in cervical precancer and cancer among Native American, Hispanic and non-Hispanic women of the southwest and on a global basis. She has overseen a number of large-scale multidisciplinary population-based projects that have ultimately enabled advances in primary (HPV vaccines) and secondary cervical cancer prevention (Pap and HPV tests).  Science Daily  Original web page at Science Daily


HPV vaccine reduced cervical abnormalities in young women

Young women who received the human papillomavirus (HPV) vaccine through a school-based program had fewer cervical cell anomalies when screened for cervical cancer, found a new study in CMAJ (Canadian Medical Association Journal).

“Eight years after a school-based HPV vaccination program was initiated in Alberta, 3-dose HPV vaccination has demonstrated early benefits, particularly against high-grade cervical abnormalities, which are more likely to progress to cervical cancer,” writes Dr. Huiming Yang, Medical Officer of Health and Medical Director, Screening Programs, Alberta Health Services, Calgary, Alberta, with coauthors.

Alberta has both a school-based HPV vaccination program and a population-based screening program for cervical cancer. In 2008, the province introduced HPV vaccination for Grade 5 girls (aged 10-11) and a 3-year catch-up program for Grade 9 girls (aged 14-15); in 2014, it was expanded to include boys. The program provides 3 doses of the vaccine that protects against two strains of HPV, which account for 70% of all cases of cervical cancer.

To determine whether HPV vaccination had an impact on Papanicolaou (Pap) test results, Alberta researchers looked at data on the first cohort of women who participated in both the school vaccination program and cervical cancer screening. The 10 204 women in the study population were born between 1994 and 1997 (aged 18 to 21 years) and lived in the province before 2008.

Of the total, 1481 (14.5%) were cases — that is, they had cervical anomalies detected during screening — and the remaining 8723 (85.5%) were controls — with no cervical abnormalities detected. Among cases, most (1384, 93.5%) had low-grade cervical abnormalities, and the remaining 97 (6.5%) had high-grade abnormalities.

More than half of the study participants (56%) were unvaccinated, and 44% had received 1 or more doses of the HPV vaccine before being screened for cervical cancer. Of the women who had been vaccinated, 84% received 3 or more doses. Among the unvaccinated women, 16.1% had cervical abnormalities, compared with 11.8% in the fully vaccinated group.

The authors note that effective HPV vaccination with broad uptake will affect the harms and benefits of cervical screening.

“With population-based HPV vaccination, guidelines for cervical cancer screening may need to include a later age for screening initiation age and/or a longer interval between screenings,” they write.

The authors hope that their findings and future research will lead to improved primary and secondary prevention efforts, with integration of HPV vaccination and cervical cancer screening programs. Science Daily  Original web page at Science Daily


Anthrax capsule vaccine completely protects monkeys from lethal inhalational anthrax

Vaccination with the anthrax capsule–a naturally occurring component of the bacterium that causes the disease–completely protected monkeys from lethal anthrax infection, according to a study published online this week in the journal VACCINE. These results indicate that anthrax capsule is a highly effective vaccine component that should be considered for incorporation in future generation anthrax vaccines.

Bacillus anthracis, the bacterium that causes anthrax, is recognized as one of the most significant bioterrorism threats. It produces three main components that allow it to cause disease–lethal toxin, edema toxin, and capsule. During anthrax infection, the bacterium invades and grows to high concentrations in the host. The capsule surrounds the bacterium and prevents it from being ingested and destroyed by the white blood cells, thus allowing anthrax infection to progress. The toxins are thought to act mainly by damaging the body’s natural defense mechanisms.

Current human vaccines for anthrax are based on the protective antigen component of the anthrax toxins. Scientists at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) have extensively studied protective antigen, demonstrating that protective antigen alone confers protection in animal challenge studies with both rabbits and monkeys.

However, according to senior author Arthur M. Friedlander, M.D., of USAMRIID, concerns about reliance on a single antigen–as well as the issue of protecting against anthrax strains that may be vaccine resistant–have prompted the search for additional vaccine components. Bacterial capsules are commonly used in licensed vaccines for other diseases, including certain types of pneumonia and meningitis.

Friedlander’s group had already demonstrated in published studies that the anthrax capsule plays a role in conferring protection. In their current work, the team describes testing a higher dose of the capsule vaccine in monkeys against a lethal aerosol challenge with anthrax spores. All the animals receiving the capsule vaccine survived while all non-vaccinated animals succumbed to the disease.

“In the 140-year history of research on anthrax there have been two previous types of vaccine, the last one licensed in 1970,” Friedlander said. “This new capsule vaccine is expected to work against possible vaccine-resistant strains of anthrax and to protect individuals who may not respond optimally to protective antigen alone. In addition, it could be combined with protective antigen to create a multi-component vaccine that may enhance the efficacy of protective antigen- based vaccines.”  Science Daily Original web page at Science Daily


* World’s first vaccine developed against Toxic Shock Syndrome

Toxic Shock Syndrome (TSS) is a severe circulatory and organ failure caused by bacterial toxins, usually triggered by bacteria from the Staphylococcus group. Researchers from MedUni Vienna’s Department of Clinical Pharmacology, in collaboration with the company Biomedizinische Forschungsgesellschaft mbH in Vienna, have now developed the world’s first safe and effective vaccine against this disease and successfully tested it in a Phase I trial. The promising results were recently published in the leading journal “The Lancet Infectious Diseases.”

This syndrome was first described in the 1980s. General symptoms of sepsis or blood poisoning occurred in young women who had used so-called “super tampons” during their periods. This is why the syndrome was also known as “tampon disease.” This subsequently led to the absorption capacity of tampons being regulated.

Staphylococci colonize nearly all of us, especially on our skin and mucous membranes. They are totally harmless to most people. “However, for people with weakened immune systems, they can cause serious diseases such as Toxic Shocks Syndrome,” explains Martha Eibl, director of Biomedizinische Forschungsgesellscaft mbH and former university professor at the Institute for Immunology of the medical faculty of the University of Vienna. This affects dialysis patients, the chronically sick, people with liver diseases and people recovering after heart operations. “Nevertheless, in 50% of cases the disease is associated with menstruation in young women,” says Bernd Jilma from MedUni Vienna’s Department of Clinical Pharmacology.

The vaccine, which has now been found to be safe and effective — and to have practically no side effects — in a clinical Phase I trial, and has been tested on 46 young men and women, was developed from a detoxified Staphylococcus toxin. The vaccine is injected into the skin and its effect is similar to that of a tetanus vaccination, says Jilma. “Immunization with such vaccines lasts for five years or more.” Once vaccinated, a person develops antibodies, which become active if the germs start to pose a threat. A blood test can show whether someone is short of antibodies. Risk groups could then be preventively vaccinated.

“We are well on the way to having a vaccine that prevents this series disease. However, it will still take some years before it is in clinical use,” explains Eibl. A Phase II trial with a larger test population has now started, in order to check the initial, promising results. “We are still looking for more volunteers,” says Jilma. Science Daily Original web page at Science Daily


Putting the brakes on cell’s ‘engine’ could give flu, other vaccines a boost

A relatively unknown molecule that regulates metabolism could be the key to boosting an individual’s immunity to the flu — and potentially other viruses — according to research reported today in the journal Immunity.

The study, led by University of Vermont (UVM) College of Medicine doctoral student Devin Champagne and Mercedes Rincon, Ph.D., a professor of medicine and an immunobiologist, discovered that a protein called methylation controlled J — or MCJ — can be altered to boost the immune system’s response to the flu.

Metabolism is a crucial function that helps keep cells alive. It plays a role in a range of bodily processes — from the conversion of food into energy to the ability to fight off infection. MCJ is the part of the cell that produces energy and enables metabolism.

“It’s the engine of the cell,” says Rincon, who adds that previously, researchers assumed that the mitochondria were constantly active.

She and Champagne discovered that MCJ acts as a braking system in the mitochondria, slowing these organelles down. Without MCJ, the mitochondria are hyperactive.

In the T cells of the body’s immune system, specifically the CD8 T cells that fight viruses and infections, metabolism helps ensure that those bug-fighting cells remain active and don’t tire out. When a virus attacks, CD8 cells detect and kill it while leaving the healthy cells intact.

MCJ controls the metabolism of the CD8 cells. It prevents the mitochondria from generating too much energy and making the CD8 cells so overactive that they kill healthy cells.

A vaccine, such as a flu shot, trains the CD8 cells to identify that virus and destroy it. With a good vaccine, the CD8 cells will “remember” and protect against that virus for a long time.

“The metabolism of immune cells is very important,” explains Rincon. “It is critical to determining effective protection against infection, but also if vaccines will work,” she says.

For their study, Champagne and Rincon generated mutant mice without MCJ and infected both normal mice and mice lacking MCJ with flu virus — imitating a vaccine, so the animals’ CD8 cells would learn to recognize the bug. After four weeks, they took the CD8 cells from the infected mice and injected those cells into other mice. One group received normal CD8 cells; the other group got cells without MCJ.

The researchers gave those new mice very high doses of the same flu virus. The mice with normal CD8 cells all died from the virus, indicating that the “educated” CD8 cells did poorly in protection. In contrast, the mice injected with MCJ-deficient CD8 cells had proper protection and all survived.

Champagne and Rincon concluded that with normal MCJ levels, CD8 cells are not as efficient in fighting virus because their mitochondrial metabolism is not strong enough, so the removal of MCJ (the “mitochondrial brake”) can improve the CD8 cells protection capability — and thus the efficacy of a vaccine.

“Nothing has been shown to do what this protein does,” says Rincon. “Suppressing MCJ will enhance your immune response and protection from an influenza virus and, most likely, protection from other threatening viruses.”

The researchers are now testing potential therapies for fatty liver disease by eliminating MCJ in liver cells. That action speeds up the metabolism process of breaking down lipids and converting fat into energy, thus reducing the presence of the disease, which affects 15 to 20 percent of humans, Rincon says. Science Daily Original web page at Science Daily


Long-term survival achieved in metastatic melanoma with personalized vaccine

Robert O. Dillman, MD, formerly Vice President Oncology, Caladrius Biosciences, Inc. and currently Chief Medical Officer, NeoStem Oncology (Irvine, CA) and Executive Medical and Scientific Director, Hoag Cancer Institute (Newport Beach, CA) discusses the typically poor prognosis for patients with melanoma of the eye or skin that spreads to the liver, and reports on the potential to achieve long-term survival without disease progression in a subset of patients using the eltrapuldencel-T vaccine. One patient had no disease progression for more than 4.5 years, while the other patient survived and remained disease-free for more than 12 years.

The article “Long-term Progression-free and Overall Survival in Two Melanoma Patients Treated with Patient-Specific Therapeutic Vaccine Eltrapuldencel-T After Resection of a Solitary Liver Metastasis” provides a detailed discussion of the composition and use of the vaccine and its effectiveness in these patients.

“These exciting results illustrate the potential for melanoma patient-specific therapeutic vaccines to enhance long-term survival and add to the progress being made on the immmunotherapy of melanoma,” says Co-Editor-in-Chief Donald J. Buchsbaum, PhD, Department of Radiation Oncology, Division of Radiation Biology, University of Alabama at Birmingham. Science Daily Original web page at Science Daily


* First ever vaccine for deadly parasitic infection may help prevent another global outbreak

As scientists scramble to get a Zika virus vaccine into human trials by the end of the summer, a team of researchers is working on the first-ever vaccine to prevent another insect-borne disease — Leishmaniasis — from gaining a similar foothold in the Americas.

Leishmaniasis is a parasitic infection passed on through the bite of a sand fly. Using breakthrough CRISPR-cas9 gene editing technology, the researchers — hailing from Japan, Brazil, Canada and the United States — have altered the parasite’s DNA to create a live-attenuated vaccine. If approved, the vaccine will be the first ever to combat a parasite.

“The Ebola and Zika outbreaks show how so-called ‘neglected’ tropical diseases can quickly turn into global public health issues,” says principal investigator Abhay Satoskar, MD, PhD , a microbiologist at The Ohio State University Wexner Medical Center and Center for Microbial Interface Biology. “This vaccine, which has been more than twenty years in the making, could give us the opportunity to stop Leishmania infections before they start, and prevent the type of global spread we’ve seen with other diseases.”

The parasitic protozoa typically causes disfiguring skin infections, but can also silently lurk in the bloodstream, hiding in immune cells and lodging in the spleen, liver and bone marrow with often fatal results. Out of the two million people who are infected each year, 50,000 will die. Current treatments have toxic side effects and are expensive, making effective control of Leishmaniasis in resource-scarce communities difficult. The parasite has also begun to develop resistance against the therapies.

While Leishmaniasis is primarily found in developing nations in Asia, the Middle East and Central and South America, cases have begun to crop up along the southern US border and in Puerto Rico. Thousands of troops from Desert Storm and other Middle Eastern military campaigns have returned with the disease. Sporadic outbreaks in dog kennels across the United States (the parasite is easily transferred between animals and humans) also has public health experts watching closely.

“The sand fly is here. Millions of people travel each year to areas with Leishmaniasis and 90% of those who are infected with the visceral form of the infection don’t have any symptoms,” says co-investigator Hira Nakhasi, PhD, a researcher with the US Food & Drug Administration (FDA) who has been studying Leishmaniasis for decades in order to keep the nation’s blood supply parasite-free. “Diseases don’t recognize borders. Either we can stop Leishmaniasis before it gets here, or we can try to deal with it after. We’re hopeful this vaccine will give us a good head start.”

The idea that a vaccine could be developed for Leishmaniasis is not new. For hundreds of years, rural communities have observed that people who had Leishmaniasis skin infections (which typically do not require medical intervention) were less likely to get the deadly, visceral form of the parasite. Some cultures adopted a crude vaccination method where disease-free children were deliberately exposed to pus from sores to establish immunity — a tradition that has carried over into modern times.

“The Leishmanization process practiced by these villages gave us the idea that a vaccine was possible, but we also wanted to truly understand how and why this immune memory develops,” says Satoskar.

As one of the first steps, the team created the first animal model of visceral leishmaniasis using natural mode of infection through an infected sand fly bite. Previously, Nakhasi’s lab at the FDA made a critical discovery that Leishmanias growth is dependent on the production of a protein called centrin in the amastigote form of the parasite which is responsible for infectivity. When the gene that triggers centrin production is removed, the parasite is unable to develop, and is cleared out of the immune cells within a few weeks.

Further, Nakhasi’s lab successfully removed the centrin gene from a deadly strain of Leishmania and used it to create a live-attenuated vaccine that ultimately protected dogs, hamsters and mice from the deadly visceral type of Leishmaniasis. The group, along with Dr. Satoskar’s lab, showed that this live-attenuated vaccine also provided cross-protection against the two other types of Leishmanias that cause non-deadly skin infections. Recently, the Canadian member of the research team removed the centrin gene from the Leishmanias that cause non-deadly skin infections using CRISPR-Cas9 gene editing technology and showed that they do not cause skin infections in mice.

There are inherent risks with live-attenuated vaccines, which use a weakened version of the pathogen in order to trigger an immune response without causing full blown disease. But the researchers are confident that the vaccine based on the altered Leishmaniasis parasites could join a line of successful live-attenuated vaccines that have been used to control yellow fever, polio, Rubella, Measles, Mumps and smallpox.

“The team’s cross-functional expertise in immunology, microbiology, parasitology and genetics along with a deep understanding of vaccine manufacturing methods means we aren’t just creating a vaccine that works, but all of the biomarker tests needed to ensure it’s safe and effective,” says Nakhasi.

The team has already identified a manufacturer in India that is capable of making the live-attenuated vaccine and meets FDA production standards. India bears about 80% of the world’s Leishmaniasis burden.

“It’s one thing to create a vaccine in a sterile, academic lab,” says Satoskar. “When we can do it successfully in resource-scarce areas, it helps ensure greater access for people who need it the most,”

The vaccine wasn’t designed to work in just animal models, but also to be effective against natural infection through sand fly bites. Past research has shown that sand fly saliva contains a protein that slows the human immune system down, which gives the parasite a better chance at surviving. Many studies so far simply start an infection by delivering the parasite via intravenous injection (IV), but this method does not measure the potential immune impact of the sand fly saliva.

In the last few years the team has pioneered procedures that emulate the sand fly bite in order to better understand the role saliva has in producing an immune response, and importantly, antibodies against future infection.

In a study recently published in PLoS Neglected Tropical Diseases, the team discovered that a vaccine augmented with a salivary protein delivered via the skin provided a better immunity against visceral Leishmaniasis than just the vaccine or the salivary protein alone.

“It’s not enough to simply find a vaccine that works. We want to know the exact mechanisms that are generating immunity, how and why,” says Satoskar. “That increases our likelihood of developing a safe, effective vaccine and the diagnostics needed to measure both.” The team expects human trials of the vaccine to begin within the next five years.  Science Daily  Original web page at Science Daily


Researchers push for personalized tumour vaccines

It is precision medicine taken to the extreme: cancer-fighting vaccines that are custom designed for each patient according to the mutations in their individual tumours. With early clinical trials showing promise, that extreme could one day become commonplace — but only if drug developers can scale up and speed up the production of their tailored medicines.

The topic was front and centre at the American Association for Cancer Research (AACR) annual meeting in New Orleans, Louisiana, on 16–20 April. Researchers there described early data from clinical trials suggesting that personalized vaccines can trigger immune responses against cancer cells. Investors seem optimistic that those results will translate into benefits for patients; over the past year, venture capitalists have pumped cash into biotechnology start-ups that are pursuing the approach.

But some researchers worry that the excitement is too much, too soon for an approach that still faces many technical challenges. “What I do really puzzle at is the level of what I would call irrational exuberance,” says Drew Pardoll, a cancer immunologist at Johns Hopkins University in Baltimore, Maryland.

The concept of a vaccine to treat cancer has intrinsic appeal. Some tumour proteins are either mutated or expressed at different levels than in normal tissue. This raises the possibility that the immune system could recognize these unusual proteins as foreign — especially if it were alerted to their presence by a vaccine containing fragments of the mutated protein. The immune system’s army of T cells could then seek out and destroy cancer cells bearing the protein.

Decades of research into cancer-treatment vaccines have thus far yielded disappointing clinical trial results, but recent advances — including a suite of drugs that may amplify the effects of cancer vaccines — have rekindled hope for the field. And DNA sequencing of tumour genomes has revealed a staggering diversity of mutations, producing proteins that could serve as ‘antigens’ by alerting the immune system.

Last year, researchers reported that they had triggered an immune response in three patients with melanoma by administering a vaccine tailored to their potential tumour antigens. The vaccines’ effects on tumour growth are not yet clear, but by the end of 2015, several companies had announced their intention to enter the field. Gritstone Oncology, a start-up firm in Emeryville, California, raised US$102 million to pursue the approach, and Neon Therapeutics of Cambridge, Massachusetts, raised $55 million. A third company, Caperna, spun out of a prominent biotechnology company called Moderna Therapeutics, also in Cambridge.

Academic groups are also moving quickly. At the AACR meeting, Robert Schreiber of Washington University in St. Louis described six ongoing studies at his institution in cancers ranging from melanoma to pancreatic. Cancer researcher Catherine Wu of the Dana-Farber Cancer Institute in Boston, Massachusetts, also presented data from a trial in melanoma, showing signs of T-cell responses to the vaccine.

But it takes Wu’s team about 12 weeks to generate a vaccine, and the Washington University team needs about 8 weeks. That could limit the treatment to slow-growing cancers, says Wu.

There is also a reason that so many researchers choose melanoma for proof-of-principle trials. Melanoma tumours tend to harbour many mutations — sometimes thousands — which provide scientists with ample opportunity to select those that may serve as antigens. Some researchers worry that tumours with fewer mutations may not be as suitable for personalized vaccines.

But Schrieber notes that researchers have been able to design a vaccine for a woman with the brain tumour glioblastoma — which often has relatively few mutations. In that case, however, the tumour had many mutations, some of which may have been caused by her previous cancer treatment.

The number of potential antigens could be crucial. At the AACR meeting, Ton Schumacher, an immunologist at the Netherlands Cancer Institute in Amsterdam, noted that many of the mutant proteins that his group has found are not required for tumour survival. As a result, a tumour could maintain its cancerous lifestyle but become resistant to the vaccine if the proteins used to design the vaccine mutate again. “We will need to attack tumours from many different sides,” he says.

Pardoll, meanwhile, is concerned that the field is shifting too quickly to the personalized-vaccine approach and leaving behind decades of research on antigens that might be shared across tumours — an approach that has not borne out in clinical trials thus far, but would be much simpler to manufacture and deploy on a large scale. “I will be the happiest person in the world to be proven wrong on these,” he says of personalized vaccines. “But I think one has to nonetheless be cognizant of where the challenges are.”

Nature 532, 425 (28 April 2016) doi:10.1038/nature.2016.19801  Nature  Original web page at Nature


New mouse model to aid testing of Zika vaccine, therapeutics

A research team at Washington University School of Medicine in St. Louis has established a mouse model for testing of vaccines and therapeutics to battle Zika virus.

The mouse model mimics aspects of the infection in humans, with high levels of the virus seen in the mouse brain and spinal cord, consistent with evidence showing that Zika causes neurological defects in human fetuses. Interestingly, the researchers detected the highest levels of the virus in the testes of male mice, a finding that supports clinical data indicating the virus can be sexually transmitted. The new research is published April 5 in Cell Host &Microbe.

“Now that we know the mice can be vulnerable to Zika infection, we can use the animals to test vaccines and therapeutics — and some of those studies are already underway — as well as to understand the pathogenesis of the virus,” said senior author Michael Diamond, MD, PhD, a professor of medicine at Washington University.

The new model of Zika virus infection, along with another recently identified by scientists at the University of Texas Medical Branch, are the first to be developed since 1976. The earlier models were not as clinically relevant because the infections were generated by injecting the virus directly into the brain. In the new models, infection occurs via the skin, much like the bite of the mosquito that spreads the virus.

The ongoing Zika virus outbreak in Latin America and the Caribbean has created an urgent need for identifying small animal models as a first step toward developing vaccines and treatments to fight the infection. The infection has been linked to microcephaly, a condition in which infants are born with unusually small heads and brain damage. In adults, the virus is thought to be related to rare cases of Guillian-Barré syndrome, an illness that can cause temporary paralysis.

For the new study, researchers in Diamond’s laboratory, led by first author Helen Lazear, PhD, now at the University of North Carolina at Chapel Hill, tested five strains of the Zika virus in the mice: the original strain acquired from Uganda in 1947; three strains that circulated in Senegal in the 1980s; and the French Polynesian strain, which caused infections in 2013 and is nearly identical to the strain causing the current outbreak. All yielded similar results in the animals, suggesting that there may not be much difference in the pathogenicity between individual strains, at least in this mouse model. Tests with the viral strains from the current Zika outbreak are ongoing.

Because Zika typically has trouble establishing infections in mice, the researchers used animals that were genetically altered so that they could not produce interferon, a key immune system signaling molecule, thus dampening the animals’ immune response to the virus.

“If you take away interferon, the Zika virus replicates quite well in the mouse and goes to the sites that we see it causing disease in humans,” said Diamond, an expert in viral immunology. He also is a professor of molecular microbiology and of pathology and immunology.

The immune-deficient mice lost weight, became lethargic and died within 10 days of infection. In contrast, normal laboratory mice included in the study only developed severe symptoms of Zika infection if they were infected soon after birth, under one week of age, before their immune systems were developed.

That finding parallels what is seen in humans. “It appears that pregnant women infected with Zika can pass the virus to babies in utero and that newborns also may be susceptible to infection,” said Diamond, also an associate director of the university’s Center for Human Immunology and Immunotherapy Programs. “Other than in infants, we don’t really see severe disease in most people with Zika, except for a small fraction who develop Guillian-Barré.”

He was inspired to pursue Zika research after a meeting at the National Institutes of Health (NIH) in June 2015, where Brazilian scientists described accounts of a rise in birth defects related to a local Zika outbreak. He returned to St. Louis and shifted several members of his lab to studying Zika, including developing mouse models of the disease.

As new clinical information becomes available about the virus in humans, Diamond has pivoted his research to investigate suspected links in mice.

“We looked for evidence of Zika in the mouse testes mostly as an afterthought, due to mounting evidence of sexual transmission and were surprised that viral levels were the highest we saw in any tissue,” Diamond noted. “We are now doing subsequent tests to determine how long those viral levels are sustained, which could help us estimate the length of time Zika can be transmitted sexually.”  Science Daily Original web page at Science Daily


HIV vaccine candidate confirms promise in preclinical study

Mymetics Corporation (OTCQB: MYMX), a pioneer in the research and development of virosome-based vaccines to prevent transmission of human infectious diseases across mucosal membranes, has announced that its innovative HIV vaccine candidate has shown to generate significant protection in groups of twelve female monkeys against repeated AIDS virus exposures during part of the preclinical study.

The blinded study was led by Dr. Ruth Ruprecht, Scientist & Director of the Texas Biomed AIDS Research Program and was funded by the Bill & Melinda Gates foundation. During the first part of the study the Mymetics’ two-component virosome-based HIV vaccine was able to show significant efficacy of 87% in delaying the time to persistent infection versus the control group after 7 intravaginal virus challenges. The study aimed to mimic the exposure of women to semen from HIV-infected men, although the viral dose of each of these 7 animal challenges represented about 70,000 times the average human HIV dose passed during sexual intercourse from an HIV-infected male to an uninfected female.

During the second part of the study the animal viral challenge dose was increased by 50% starting from the 8th challenge onward, reaching more than 100,000 times the average amount of virus passed from an infected man to a female partner. At this virus dose, the vaccine did not show significant protection in the animals as the immune system was overloaded.

Dr. Ruth Ruprecht said, “We are encouraged by the initial strong protection provided by the vaccine candidate, which is in line with the results from an earlier primate study performed in China that we were asked to repeat. The fact that the vaccine-induced immune defenses were eventually overcome requires a careful analysis to understand the mechanisms of the initial vaccine action and to learn what other immune defenses can be enlisted to yield even more potent antiviral action.”

Sylvain Fleury, CSO of Mymetics, commented, “We are pleased that Mymetics HIV virosome-based vaccine could strongly prevent virus transmission under conditions that mimic male-to female sexual transmission. Especially as these protection results are coming from two studies conducted in two different countries, with two different sub-species of macaques, with different vaccine lots and without an adjuvant. The observed protection in genetically different animals raised in different housing and environmental conditions gives more weight to these observations.”

Ronald Kempers, CEO of Mymetics, “We were very impressed with the professional and thorough work delivered by Dr. Ruprecht’s team, including Dr. Samir Lakhashe, Staff Scientist at Texas Biomed, and look forward to understanding the mechanisms of action of our vaccine. This study proves that our HIV vaccine candidate can protect in very realistic settings and it provides a strong indication to possibly protect women against sexually transmitted HIV and come closer to an effective HIV vaccine in the future. Virosomes have a strong safety profile in children and adults and our virosome construct can easily be combined with other vaccine candidates and treatments, therefore we are hopeful that we can attract funding for the clinical development and move a step closer to an HIV vaccine.”

The study involved 36 Indian origin rhesus macaques (monkeys) with 12 animals per group for more statistical power, compared two antigen vaccination regimens with placebo and was followed by intra-vaginal heterologous challenges with live virus.

This study was designed to replicate a successfully completed smaller study at the Institute of Laboratory Animal Science (ILAS) in Beijing, China in which the two-component vaccine protected all Chinese rhesus macaque monkeys against repeated virus exposures from persistent infection — an unprecedented result. One of the vaccine components further showed a strong safety and tolerance profile in a Phase I clinical trial in human volunteers.

With its HIV-1 (human immunodeficiency virus type 1) vaccine candidate, produced through its proprietary virosome technology, Mymetics aims to provide both a first line of defense through mucosal protection as well as a second line of defense against infection through the generation of blood antibodies. Mymetics has produced the tested HIV vaccine construct for clinical trials in liquid form and, since last year, is developing a new generation of needle-free and cold chain independent virosomal vaccine construct with the support of the European Horizon 2020 Program (MACIVIVA Project no. 646122), which would be very suitable for developing countries. Science Daily  Original web page at Science Daily


First in-human vaccine study for malaria caused by Plasmodium vivax

Walter Reed Army Institute of Research (WRAIR) researchers recently published the results of testing a Plasmodium vivax malaria vaccine candidate in a human challenge model.

A vaccine to prevent infection and disease caused by P. vivax is critical to reduce sickness and mortality from vivax malaria, a common cause of malaria among deployed service members. While malaria no longer poses a significant threat in developed countries, it affects millions of people every year around the world. P. vivax malaria is challenging to control because it can be dormant, causing no symptoms, and then become active causing symptomatic malaria weeks to months after initial infection.

The vaccine candidate developed by WRAIR and tested jointly with GlaxoSmithKline (GSK) to prevent vivax malaria infection is the first in-human study of its kind under an investigational new drug application with the US Food and Drug Administration. WRAIR investigators immunized 30 volunteers with three doses of the vaccine candidate. Malaria is only transmitted through the bite of a female mosquito. Immunized volunteers took part in WRAIR’s well-established controlled human malaria infection (CHMI) model where they were bitten by malaria-infected mosquitoes. The efficacy of the vaccine candidate was then determined based on whether or not volunteers developed malaria by looking at blood smears or if it took longer for malaria parasites to appear in the blood.

“This study represents the first vaccine study to test the effectiveness of a P. vivax vaccine candidate in humans using controlled human malaria infection,” said Lt. Col. Jason W. Bennett, the study’s lead investigator. The study’s results were published today in the journal PLOS Neglected Tropical Diseases. Unlike P. falciparum where a CHMI model is well established, the P. vivax CHMI model must rely on blood donations from infected humans to initiate infections in mosquitoes.

For this trial, the WRAIR investigators worked with the WRAIR overseas lab in Bangkok, Thailand, the Armed Forces Research Institute of Medical Sciences (AFRIMS), to acquire P. vivax-infected mosquitoes which were then transported to WRAIR for the malaria challenge. The vaccine candidate was well tolerated in all volunteers and generated robust immune responses. While the vaccine candidate did not prevent malaria infection, it did significantly delay parasitemia in 59% of vaccinated subjects.

Col. Robert Paris, director of the US Military Malaria Research Program at WRAIR, is optimistic that an improved vaccine can be designed. “Findings from the analysis of the immune response of vaccinated subjects have given us clues to improve vaccine candidates and studies are now underway at WRAIR to develop next generation vivax vaccines,” says Dr. Paris, “Vaccines and antimalarial drugs are both critical needs for the DoD to protect service members from malaria.”

Malaria challenge models require effective treatment for any resulting malaria infections. Investigators were also able to demonstrate that individuals with low or absent levels of a specific liver enzyme were unable to convert primaquine to an active drug form to kill the dormant stage of the parasites. These volunteers were more likely to experience vivax malaria relapse. The clinical data in this study is the first to show that differences in a person’s genetics can result in primaquine treatment failure. Despite this newly identified limitation, primaquine remains the only FDA-approved drug to treat the dormant stages of vivax malaria.

WRAIR remains dedicated to developing vaccines, cures, and other products to eradicate and curb the transmission of infectious diseases. Decades of research at WRAIR have culminated in many effective products, including vaccines for yellow fever, dengue fever, and Japanese encephalitis. This study demonstrates WRAIR’s continued dedication to malaria prevention and marks an important step towards an effective P. vivax vaccine.  Science Daily  Original web page at Science Daily


Effectiveness of a herpesvirus CMV-based vaccine against Ebola

This study represents a crucial step in the translation of herpesvirus-based Ebola virus vaccines into humans and other great apes. As the latest in a series of studies, researchers at Plymouth University, National Institutes of Health and University of California, Riverside, have shown the ability of a vaccine vector based on a common herpesvirus called cytomegalovirus (CMV) expressing Ebola virus glycoprotein (GP), to provide protection against Ebola virus in the experimental rhesus macaque, non-human primate (NHP) model. Demonstration of protection in the NHP model is regarded as a critical step before translation of Ebola virus vaccines into humans and other great apes.

The study is published Monday 15th February, in the online journal from Nature publishing, Scientific Reports.

In addition to establishing the potential for CMV-based vaccines against Ebola virus, these results are exciting from the potential insight they give into the mechanism of protection. Herpesvirus-based vaccines can theoretically be made to produce their targeted protein (in this case, Ebola virus GP) at different times following vaccination. The current CMV vaccine was designed to make the Ebola virus GP at later times. This resulted in the surprising production of high levels of antibodies against Ebola virus with no detectable Ebola-specific T cells. This immunological shift towards antibodies has never been seen before for such primate herpesvirus-based vaccines, where responses are always associated with large T cell responses and poor to no antibodies.

“This finding was complete serendipity,” says Dr Michael Jarvis who is leading the project at Plymouth University. “Although we will definitely need to explore this finding further, it suggests that we may be able to bias immunity towards either antibodies or T cells based on the time of target antigen production. This is exciting not just for Ebola, but for vaccination against other infectious as well as non-infectious diseases.”

A largely untold story is the devastating effect Ebola virus is having on wild great ape populations in Africa. Although the present study administered the vaccine by direct inoculation, a CMV-based vaccine that can spread from animal to animal may be one approach to protect such inaccessible wild animal populations that are not amenable to vaccination by conventional approaches. The current study is a step forward, not only for conventional Ebola virus vaccines for use in humans, but also in the development of such ‘self-disseminating vaccines’ to target Ebola in great apes, and other emerging infectious diseases in their wild animal host before they fully establish themselves in humans.  Science Daily  Original web page at Science Daily


Much of the devastation wrought by Ebola in West Africa might have been prevented with a vaccine

With the Ebola outbreak in West Africa stubbornly hanging on, officials have brokered an agreement to ensure that a vaccine is available to fight future occurrences. On 20 January, Gavi, the Vaccine Alliance, announced that it has paid US$5 million to Merck, the manufacturer of the first Ebola vaccine shown to protect against the virus in a human clinical trial. The deal marks the first time that the public-health organization has committed to purchase a vaccine before it has been licensed.

In return for the payment from Gavi, Merck promises that it will seek to have the vaccine approved by a regulatory agency by 2017. The company has also asked permission from the World Health Organization (WHO) to use the vaccine if another epidemic arises before the vaccine is licensed, and to make a supply of at least 300,000 doses available by May for such use. “We wanted to make sure there was vaccine that was prepared and ready to be used if there was a potential outbreak,” says Seth Berkley, chief executive of Gavi in Geneva, Switzerland.

The recurrence of Ebola in Sierra Leone on 15 January — just one day after the WHO had declared that spread of the virus had stopped in West Africa — highlights the need for an Ebola vaccine stockpile, Berkley says. “It basically says we need to have a supply of vaccine available for potential outbreaks going forward, even if we get it completely under control and think we’ve ended the problem,” Berkley explains.

Public-health experts fear that as the West Africa epidemic winds down, there is danger that the work of stockpiling, licensing and planning to administer Ebola vaccines will be set aside in favour of more pressing — and profitable — pursuits.

“We are in the most tenuous situation with regard to Ebola vaccines that we’ve seen since we started all of this,” says Michael Osterholm, a public-health scientist at the University of Minnesota’s Center for Infectious Disease Research and Policy in Minneapolis.

A vast store of Ebola vaccines has been manufactured in the past year — approximately 2 million doses of three candidate vaccines made by Merck, Johnson & Johnson and GlaxoSmithKline. So far, more than 20,000 people have been vaccinated with these products, and thousands more will receive them in the coming months. Before the West Africa outbreak, only a handful of people had ever received a vaccination against Ebola. The existing supply should, at least in theory, be enough to provide crucial protection in a future outbreak for patients, their contacts and health-care workers, says Marie-Paule Kieny, assistant director-general for health systems and innovation at the WHO in Geneva.

But in practice, it remains unclear how those vaccines might be delivered during an outbreak. The biggest barrier is bureaucratic: none of the three vaccines has been submitted for approval by a regulatory body such as the US Food and Drug Administration or the European Medicines Agency. Sierra Leone and Guinea have made arrangements with the relevant companies to use the vaccines in clinical trials. But if Ebola were to arise elsewhere, negotiating similar agreements in new countries could delay the outbreak response.

Médecins Sans Frontières (MSF; also known as Doctors Without Borders), which administered the Merck vaccine trial in West Africa, plans to continue using the vaccines in investigative mode if another outbreak occurs. That means spending extra time and money compared with using a licensed vaccine — patients in a trial must be informed of the risk of taking an unapproved product, and providers must keep strict records of how well the vaccines work and whether they cause side effects. And if the vaccine is already known to be effective, this approach might also not be the right way to proceed from an ethical standpoint.

The Gavi agreement is intended to ease that problem by requiring Merck to seek an ’emergency use assessment and listing’ — permission from the WHO to use the vaccine wherever it is needed without having to organize a clinical trial. Gavi says that Merck has already begun those discussions with the WHO, and that ultimately it might buy other vaccines if they are approved.

The deal also addresses a problem facing drug companies: Ebola and other tropical diseases still mainly afflict people in poor countries, so there is little financial incentive to produce vaccines against them. The funding from Gavi to Merck is an ‘advance market commitment’ — a guarantee that Gavi will buy the vaccine once it is approved. “It says the company is not going to be left holding the bag,” Berkley says.

Nature doi:10.1038/nature.2016.19186  Nature  Original web page at Nature


Why the flu vaccine is less effective in the elderly

Around this time every year, the flu virus infects up to one-fifth of the U.S. population and kills thousands of people, many of them elderly. A study published by Cell Press on Dec. 15, 2015 in Immunity now explains why the flu vaccine is less effective at protecting older individuals. More broadly, the findings reveal novel molecular signatures that could be used to predict which individuals are most likely to respond positively to vaccination.

“We provide novel evidence of a potential connection between the baseline state of the immune system in the elderly and reduced responsiveness to vaccination,” say co-senior study authors Shankar Subramaniam of the University of California, San Diego, and Bali Pulendran of Emory University. “By providing a more complete picture of how the immune system responds to vaccination, our findings may help guide the development of next-generation vaccines that offer long-lasting immunity and better protection of at-risk populations.”

Flu vaccines, which contain proteins found in circulating viral strains, offer protection by eliciting the production of antibodies — proteins that help the immune system identify pathogens and protect against infectious disease. While vaccination is considered the most effective method for preventing influenza, it is less effective in the elderly. But until now, the molecular mechanisms underlying this decrease in vaccine efficacy were unknown.

To address this question, Subramaniam and Pulendran identified molecular signatures of immunity to flu vaccination using systems biology approaches, which involve the computational and mathematical modeling of complex biological systems. They vaccinated 212 subjects, including 54 elderly individuals, across five influenza vaccine seasons, from 2007 to 2011, and analyzed blood samples to identify molecular pathways associated with protective antibody responses elicited by vaccination. They also analyzed previously published data for 218 additional subjects.

Using this approach, the researchers identified molecular signatures present in blood samples collected a few days after vaccination that predicted with 80% accuracy whether the vaccine would elicit immune protection approximately four weeks later. Within one week of flu vaccination, young individuals showed high levels of antibody-producing B cells, whereas the elderly showed high levels of immune cells called monocytes, which elicit inflammatory responses in the body. These age-related differences predicted impaired vaccine-induced immune responses observed in the elderly three weeks later. “Together, these results suggest potential mechanisms by which changes to the innate response in the elderly may result in diminished antibody responses to vaccination,” Subramaniam says.

Even before vaccination, high baseline levels of B cells, in conjunction with low levels of monocytes and related inflammatory molecules, predicted vaccine-induced immune protection four weeks later. “This supports the concept that inflammatory responses at baseline may be detrimental to the induction of vaccine-induced antibody responses,” Subramaniam says. “While it is early to suggest, supplementary therapeutic approaches, such as reducing the inflammatory response in elderly patients after vaccination, would be valuable avenues to pursue. However, this warrants longer and more detailed investigations.”

For their own part, the researchers plan on applying similar system biology approaches to study other viral infections, such as shingles and yellow fever. “Analyzing these myriad ‘omics’ data in conjunction with physiological measurements is novel and will serve as a paradigm for future studies on influenza and other infections.”

In the meantime, they urge caution against over-generalizing their new findings. “This is obviously a complex problem, and the study reveals responses that are averaged across populations,” Subramaniam says. “As is true in every medical diagnosis, prognosis, and treatment, there is a distribution of responses with a majority conforming to the mean predicted response. So the important thing for the general audience to recognize is that there will be exceptions and variations.”  Science Daily  Original web page at Science Daily


* MERS virus: Drying out the reservoir

A German-Dutch team has succeeded in immunizing dromedaries against the MERS virus. As the camels appear to be the major reservoir of the virus, the vaccine should also reduce the risk of future outbreaks of the disease in humans.

The recently discovered coronavirus now referred to as MERS (for Middle East Respiratory Syndrome) causes an infectious respiratory disease in humans, which can be fatal. The virus is thought to be transmitted to humans primarily via contact with dromedary camels. Now researchers led by virologist Gerd Sutter at Ludwig-Maximilians-Univeritaet (LMU) in Munich, in collaboration with teams led by Professor Bart L. Haagmans of the Erasmus Medical Center (MC) in Rotterdam and Professor Albert Osterhaus of University of Veterinary Medicine Hannover, Foundation (TiHo), have successfully tested a candidate vaccine against MERS, in camels.” We have been able to show, for the first time, that our vaccine can significantly reduce the virus load in infected camels,” says Sutter. The results of the trial appear in the latest issue of the journal Science.

The new vaccine, MVA-MERS-S, was developed by Sutter and his team two years ago. In cooperation with researchers based at Philips University in Marburg and the team in Rotterdam, he introduced a gene for the so-called spike protein of MERS into the genome of a weakened strain of poxvirus (MVA). The resulting modified poxvirus particles expressed the MERS protein on the surface of infected cells, and these engineered viruses form the basis of the new vaccine. Several preliminary data over the past two years have confirmed the immunogenicity and efficacy of MVA-MERS-S in mice. The scientists now describe the outcome of the first direct test of the vaccine in camels.

The MERS virus was first identified in Saudi Arabia in 2012. To date, some 1400 cases of MERS have been reported, of which one-third proved fatal. Its primary hosts, however, are dromedary camels, as revealed by the detection of antiviral antibodies and the presence of MERS particles in the nasal cavity in infected animals. Although camels infected with the virus show relatively mild symptoms, all the evidence suggests that they can transmit the pathogen to humans, who can subsequently pass it on to others. Hence, vaccination of camels against MERS virus is an obvious method of choice for the prevention of human infections. Successful immunization would deprive the virus of its primary host and break the chain of transmission, effectively minimizing the risk of future MERS epidemics in human populations.

But the vaccine from Sutter’s laboratory actually turns out to another advantage: “Immunization with MVA-MERS-S simultaneously protects camels from camelpox, a disease similar to smallpox in humans — which can be life-threatening in dromedaries,” Bart L. Haagmans of the Erasmus Medical Center explains.

In camels infected with the MERS virus, symptoms of disease are confined to the upper respiratory tract. In the new study, the researchers infected a total of 8 camels. Half of these had been immunized, both intranasally and intramuscularly, with MVA-MERS-S three weeks prior to exposure to the virus. “In this group of animals, the vaccine had induced the development of sufficient amounts of antibodies to inhibit viral multiplication and prevent the appearance of disease symptoms upon infection,” says Dr. Asisa Volz, a member of Prof. Sutter’s group. In addition, anti-MERS antibodies were detected in both the nasal mucosa and in the bloodstream of immunized animals. The controls, on the other hand, which were injected with poxviruses particles lacking the S protein, exhibited the typical runny nose, and infectious virus was readily detectable in nasal secretions. “Our results clearly show that vaccination with MVA-MERS-S markedly reduces the numbers of viruses present in the nasal epithelia of camels,” says Albert Osterhaus of University of Veterinary Medicine Hannover.

MVA-MERS-S can, of course, also be used to immunize humans. Indeed, thanks to the tests carried out so far, the vaccine already meets many of the most important preconditions that must be fulfilled prior to its use in clinical trials in humans. Gerd Sutter is currently leading a project entitled “GMP manufacture and Phase I clinical investigation of MVA-MERS-S, an experimental prophylactic vaccine against the Middle East Respiratory Virus Syndrome” at the German Center for Infection Research, which is designed to set the scene for the first such tests of the vaccine in humans.

So far, there are no candidate vaccines available that could be used in the event of a large-scale epidemic. Only a few months ago, in the early summer of 2015, more than 180 people were infected with MERS in South Korea. The origin of the outbreak was traced to a single carrier, who had recently returned from the Middle East. All confirmed infections in humans have so far been linked, directly or indirectly, to that part of the world, hence the name Middle East Respiratory Syndrome Coronavirus (MERS-CoV) for the pathogen responsible. Three cases of MERS have been recorded in Germany. All three patients had recently visited Saudi Arabia, and had contracted the disease there.  Science Daily  Original web page at Science Daily


Towards a safe and efficient SARS-coronavirus vaccine: Mechanism and prevention of genetic instability of a live attenuated virus

Live attenuated (weakened) viral vaccines are considered safe so long as their “reversal” to a virulent (or disease-causing) virus is prevented. A study published on October 29th in PLOS Pathogens reports on how to rationally modify an effective live attenuated SARS vaccine to make it genetically stable.

Luis Enjuanes, from the Centro Nacional de Biotecnología in Madrid, Spain, and colleagues had previously introduced a SARS-CoV lacking the envelope (or E) gene as a promising vaccine candidate. The researchers had shown that this vaccine, which they called SARS-CoV-ΔE, was attenuated in different animal models, indicating that the E protein is necessary for the virus’ ability to cause disease. They had also demonstrated that vaccination with SARS-CoV-ΔE fully protected mice against challenge with virulent SARS-CoV that is lethal in unvaccinated mice, suggesting that it is an efficient vaccine.

In this study, the researchers addressed the question of stability of the vaccine candidate. To do this, they propagated the SARS-CoV-ΔE virus for a number of generations in cell lines and in mice and found that–over time–the virus accumulates mutations and reverts to a virulent phenotype.

Studying a collection of mutants, they were able to reveal the molecular basis of the reversion: The E protein contains a motif called a PDZ binding motif or PBM, a protein-protein recognition sequence that modulates cellular pathways important for viral replication, dissemination in the host, and pathogenesis. And all the reverted viruses had incorporated in the genome a functional PBM, apparently to compensate for removal of this motif with deletion of the E protein.

To avoid such compensation and reversal to virulence, instead of deleting the entire gene, the researchers introduced small deletions in the E gene that did not destroy its PBM. Such mutants are still attenuated but appear to no longer select for the incorporation of novel protein domains into the virus genome and so avoid the reversion to virulence.

To create an additional safeguard, the researchers introduced mutations into another SARS-CoV gene called nsp1. Nsp1 was chosen as a second attenuation target because this gene is located at a distant site from that of the E gene in the viral genome, making it very unlikely that a single mutational event can restore both the E gene and the nsp1 gene to their un-attenuated sequences and thereby restore virulence.

The researchers found that small deletions within the nsp1 gene alone resulted in an attenuated virus that was unable to cause disease but protected vaccinated mice against challenge with the virulent parental virus. And when they tested the new vaccine that includes small attenuating mutations in both the E and nsp1 genes, they saw that it maintains its attenuation after prolonged propagation in vitro and in vivo and provided full-protection of mice against the challenge with the virulent original SARS-CoV.

The researchers conclude that “understanding the molecular mechanisms leading to pathogenicity and the in vivo evaluation of vaccine genetic stability contributed to a rational design of a promising SARS-CoV vaccine.” They also suggest that “understanding how an attenuated SARS-CoV reverted to virulence could also be useful for vaccine development against other relevant coronaviruses, such as the MERS-CoV.”  Science Daily  Original web page at Science Daily


Immune responses provide clues for HIV vaccine development

Recent research has yielded new information about immune responses associated with–and potentially responsible for–protection from HIV infection, providing leads for new strategies to develop an HIV vaccine. Results from the RV144 trial, reported in 2009, provided the first signal of HIV vaccine efficacy: a 31 percent reduction in HIV infection among vaccinees. Since then, an international research consortium has been searching for molecular clues to explain why the vaccine showed this modest protective effect.

A new review outlines findings that hint at the types of immune responses a preventive HIV vaccine may need to induce. The article was co-authored by leaders in HIV vaccinology, including Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and lead author Lawrence Corey, M.D., of the Fred Hutchinson Cancer Research Center.

Analyses of RV144 volunteers revealed that particular vaccine-induced immune responses, including production of certain antiviral antibodies and CD4+ T cell responses to HIV’s outer shell, or envelope, correlate with reduced HIV infection. Many RV144 vaccinees produced antibodies in the immunoglobulin G (IgG) family that bind to sites within part of the HIV envelope called V1V2. These antibodies were linked to protection against acquiring HIV. However, high levels of a different type of envelope-binding antibody belonging to the IgA family were associated with a lack of protection against HIV infection. Evidence suggests that IgA may block the protective action of IgG. Recently, monkey studies testing vaccine regimens different from those in RV144 have supported the notion that enhancing protective antibody activity may increase vaccine efficacy.

Guided by findings from human and monkey studies, researchers are working to improve upon the efficacy of the RV144 vaccine regimen. They are investigating strategies to increase the magnitude and durability of vaccine-induced immune responses associated with protection from HIV infection, as well as developing vaccines to elicit production of antibodies that are broadly neutralizing against a variety of HIV strains. As development of an effective HIV vaccine continues, efforts stemming from the modest success of the RV144 trial have “produced a momentum and series of immune targets that will hopefully lead to an effective global vaccine effort,” the authors conclude.  Science Daily  Original web page at Science Daily


New study has important implications for the design of a protective HIV vaccine

A PhD student from the University of the Witwatersrand has published a study in the journal, Nature Medicine, describing how the changing viral swarm in an HIV infected person can drive the generation of antibodies able to neutralize HIV strains from across the world. The study has important implications for the design of a protective HIV vaccine.

Jinal Bhiman, a PhD student in the Faculty of Health Sciences is the lead author of the study, titled: Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies.

The development of a vaccine remains the best possibility for ending the HIV pandemic. However, the researchers say that a major challenge has been the inability to stimulate broadly neutralizing antibodies that are able to deal with the enormous variability of HIV.

While some infected people are naturally able to make broadly neutralizing antibodies, these antibodies often have unusual features, and generally need to go through an extensive maturation process in order to acquire breadth. Studying these rare people to understand how such antibodies develop provides a roadmap for vaccine strategies.

Through a variety of “high tech” approaches, including the isolation of monoclonal antibodies from single B cells and ultra-deep sequencing of shifting viral populations over more than three years of infection, the researchers studied one woman who developed potent broadly neutralizing antibodies.

The team, led by Professors Penny Moore and Lynn Morris, was able to look back in time to identify the unique virus that bound the precursors of what would become broadly neutralizing antibodies, beginning the immune pathway to breadth.

“The study also showed how these early antibodies matured to become broadly neutralizing. As the HIV-swarm struggled to evade these potent early antibodies, it toggled through many mutations in its surface protein. This exposed the maturing antibodies to a diverse range of viruses within this single infected woman,” the researchers say.

“Antibodies exposed to this high level of viral diversity in turn mutated to be able to tolerate variation, thus acquiring the ability to neutralize diverse global viruses.”

These findings provide insights for the design of vaccines that can “kick-start” and then shape the maturation of broadly neutralizing antibodies in HIV uninfected individuals, to provide protection from HIV exposure. Science Daily  Original web page at Science Daily


Vaccination on the horizon for severe viral infection of the brain

Researchers from the University of Zurich and the University Hospital Zurich reveal possible new treatment methods for a rare, usually fatal brain disease. Thanks to their discovery that specific antibodies play a key role in combating the viral infection, a vaccine against the disease “progressive multifocal leukoencephalopathy” could now be developed.

Humans carry a multitude of viruses and bacteria in their gut, on their skin and in other organs. Often, these are involved in important bodily functions. Under certain conditions, however, some can also cause diseases. The JC virus, a member of the polyoma tumor virus family, is a prime example. This pathogen was first isolated from the brain of a patient who was suffering from a rare brain disease known as progressive multifocal leukoencephalopathy (PML). The virus, which more than 60 percent of the global population are infected with, normally resides in the kidneys and certain other organs. JC virus can trigger the PML infection in the brain, which, in most cases, is fatal.

Two studies conducted by an international team of researchers from the University of Zurich, the University Hospital Zurich, the National Institutes of Health in the USA, San Raffaele Hospital in Milan, the University of Tübingen, and the UZH spin-off Neurimmune now reveal that the antibodies in PML patients often fail to recognize the JC virus they are infected with. “In healthy people, the disease never breaks out as the immune system keeps it well under control. Once the immune system is compromised, however, such as in patients with tumors, leukemia, AIDS, autoimmune diseases and certain immunosuppressive treatments, the JC virus is able to alter its genetic information and infect the brain,” explains Roland Martin, professor of neurology at the University of Zurich.

In multiple sclerosis (MS) patients, for instance, the treatment with a particular antibody, TysabriTM, prevents immune cells from reaching the brain — but at the same time, also inhibits the brain’s immunosurveillance. If JC viruses enter the brain during the treatment, they go undetected, which can cause PML, the most significant side effect of the highly effective TysabriTM. Over 560 MS patients worldwide have already developed the PML brain infection. Over 20 percent of them died from the disease as there is no effective treatment to date. Only if the immune system function is completely restored can the JC virus be removed from the brain.

The researchers now reveal potential ways to vaccinate against PML preventatively or, if the brain has already been infected, treat it with virus-specific human antibodies. By vaccinating mice and a PML patient with the virus’ coating protein, the international groups were able to demonstrate that the antibody response was so strong that the patient was soon able to eliminate the JC virus. The so-called active vaccination method was developed at the University of Zurich and the University Hospital Zurich, and has already been used successfully on two more patients. The JC-virus-specific antibodies that are of interest for the treatment of the existing brain infection were developed by the group at the University of Zurich and the University Hospital Zurich together with colleagues from the University of Tübingen and the biotechnology company Neurimmune in Schlier.

“We made a major breakthrough,” says Martin. We managed to isolate antibody-producing cells from a patient who survived PML and use them to produce neutralizing antibodies against the JC virus. These human antibodies have a major advantage: they recognize the most important mutants of the JC virus that can cause PML. They now make promising candidates for the development of a treatment for PML.”  Science Daily  Original web page at Science Daily


* ‘Immune camouflage’ may explain H7N9 influenza vaccine failure

The avian influenza A (H7N9) virus has been a major concern since the first outbreak in China in 2013. Due to its high rate of lethality and pandemic potential, H7N9 vaccine development has become a priority for public health officials. However, candidate vaccines have failed to elicit the strong immune responses necessary to protect from infection. A study published in Human Vaccines & Immunotherapeutics has revealed that it may be due to immune camouflage

One of the ways by which the immune system detects infection is by presenting short peptides derived from the pathogen to T-cells, which distinguish between foreign and self antigens. The study shows that the H7N9 hemagglutinin (HA) surface protein has evolved a set of mutations that make it similar to human proteins, and the presented peptides thus resemble self antigens. The H7N9 influenza strain appears to effectively camouflage itself from the immune system.

“The original observation of low H7N9 T-cell epitope content was made before any data were available on vaccine efficacy,” says senior author Prof. Anne S. De Groot, Director of the Institute for Immunology and Informatics at the University of Rhode Island and CEO at EpiVax, Inc. “It turns out that we were absolutely correct. By comparison with H1N1 and H3N1, H7N9 vaccines are far less immunogenic.”

Prof. De Groot’s research team has developed a computational tool, JanusMatrix, capable of determining whether a given viral protein is similar to any human protein in residues relevant for antigen presentation.

“JanusMatrix looks at both ‘faces’ of T-cell epitopes. It starts by looking at the face that binds to HLA or MHC — the downward facing amino acids that bind into the MHC binding pockets. Having determined that a peptide can bind to a specific MHC, the program then looks at the T-cell receptor face (TCR face) and looks in a database of pre-parsed peptides from the human genome that have been identified as binding to the same MHC, for peptides that have the same TCR-facing amino acids.”

It turns out that, in addition to having low T-cell epitope content, HA from H7N9, but not from other investigated influenza strains, shows high similarity to several endogenous proteins.

The immune-camouflage hypothesis was tested by challenging peripheral blood mononuclear cells from naïve donors with H7N9-derived peptides. Remarkably, the more the peptide resembled a self antigen, the less it was able to elicit a T-cell response. In addition, the predicted human-like antigens expanded and activated regulatory T-cells that are responsible for immune suppression when endogenous peptides are presented, providing further support for the hypothesis.

“It appears that this new mechanism of immune escape may be common to quite a few human pathogens,” says Prof. De Groot. “We are working on validating several other peptides, some from common seasonal strains of influenza and some from pathogens like HIV and M. tuberculosis that do live for a long time inside their hosts.

H7N9 influenza has infected almost 670 people and led to 230 deaths, according to the U.S. Centers for Disease Control and Prevention. These findings could facilitate the development of an effective vaccine and impact vaccine research in general. “It could well explain why some candidate vaccines for pathogens that have co-evolved with human beings — like TB and HIV — do not work so well. It also suggests that ‘tweaking’ pathogen proteins to remove those camouflaging sequences would result in better, more effective vaccines,” concludes Prof. De Groot.  Science Daily  Original web page at Science Daily



* Virus-like particle vaccine protects mice from many flu strains

Each year, scientists create an influenza (flu) vaccine that protects against a few specific influenza strains that researchers predict are going to be the most common during that year. Now, a new study shows that scientists may be able to create a ‘universal’ vaccine that can provide broad protection against numerous influenza strains, including those that could cause future pandemics. The study appears in mBio, the online open-access journal of the American Society for Microbiology.

“The reason researchers change the vaccine every year is that they want to specifically match the vaccine to the particular viruses that are circulating, such as H1N1. If the vaccine is just a little bit different to the target virus, it is not expected to offer much protection,” said principal investigator of the study Jeffery Taubenberger, MD, PhD, Chief of Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID). “What we have done is design a strategy where you don’t have to think about matching the vaccine antigen to the virus at all.”

In the new study, researchers at the NIAID used a virus-like particle vaccine cocktail that expressed a handful of different subtypes of a key surface protein of the influenza virus: hemagglutinin H1, H3, H5 and H7. “There are 16 different hemagglutinin subtypes that circulate in birds and are thought to be the basis for current and future influenza pandemics,” said Dr. Taubenberger. “The hypothesis was that the presentation of these different viral proteins would stimulate the development of cross-protective immunity that would provide broader protection against multiple subtypes.”

The researchers picked the H1 and H3 subtypes because they have been the major cause of human seasonal flu outbreaks since 1918. They chose the H5 and H7 subtypes because they have been the cause of recent bird flu outbreaks and have pandemic potential. This selection also provided a broad representation of hemagglutinins across the phylogenetic tree.

In a series of experiments, the researchers found that 95% of mice vaccinated with the investigational cocktail were protected against a lethal challenge with eight different influenza strains expressing seven different influenza A subtypes, compared to only 5% of mice who received mock vaccinations.

“Almost all of the animals that were vaccinated survived, including mice that were challenged with viruses that expressed hemagglutinin subtypes that were not in the vaccine at all, viruses that expressed H2, H6, H10, and H11,” said Dr. Taubenberger. “What that suggests is that this approach really gives us broad spectrum protection, and could serve as a basis for an effective pre-pandemic vaccine.”

Additional experiments showed that the vaccine was durable, effective for at least 6 months, and that it worked well in older mice. This is important given that elderly people are particularly susceptible to severe disease following influenza infection, and current vaccines are less efficacious in the elderly than in younger people. “These initial findings are very positive and suggest a promising and practical strategy for developing a vaccine with amazing, broad protection,” said Dr. Taubenberger. Science Daily Original web page at Science Daily


* Some vaccines support evolution of more-virulent viruses

Scientific experiments with the herpesvirus such as the one that causes Marek’s disease in poultry have confirmed, for the first time, the highly controversial theory that some vaccines could allow more-virulent versions of a virus to survive, putting unvaccinated individuals at greater risk of severe illness. The research has important implications for food-chain security and food-chain economics, as well as for other diseases that affect humans and agricultural animals.

“The challenge for the future is to identify other vaccines that also might allow more-virulent versions of a virus to survive and possibly to become even more harmful,” said Andrew Read, an author of the paper describing the research, which will be published in the July 27, 2015 issue of the scientific journal PLoS Biology. Read is the Evan Pugh Professor of Biology and Entomology and Eberly Professor in Biotechnology at Penn State University.

“When a vaccine works perfectly, as do the childhood vaccines for smallpox, polio, mumps, rubella, and measles, it prevents vaccinated individuals from being sickened by the disease, and it also prevents them from transmitting the virus to others,” Read said. These vaccines are a type that is “perfect” because they are designed to mimic the perfect immunity that humans naturally develop after having survived one of these diseases. “Our research demonstrates that another vaccine type allows extremely virulent forms of a virus to survive — like the one for Marek’s disease in poultry, against which the poultry industry is heavily reliant on vaccination for disease control,” said Venugopal Nair, who led the research team in the United Kingdom where the experimental work related to this study was carried out. Nair is the head of the Avian Viral Diseases program at the Pirbright Institute, which also hosts the OIE Reference Laboratory on Marek’s disease. “These vaccines also allow the virulent virus to continue evolving precisely because they allow the vaccinated individuals, and therefore themselves, to survive, Nair said.

Less-than-perfect vaccines create a ‘leaky’ barrier against the virus, so vaccinated individuals sometimes do get sick, but typically with less-virulent symptoms. Because the vaccinated individuals survive long enough to transmit the virus to others, the virus also is able to survive and to spread throughout a population. “In our tests of the leaky Marek’s-disease virus in groups of vaccinated and unvaccinated chickens, the unvaccinated died while those that were vaccinated survived and transmitted the virus to other birds left in contact with them,” Nair said. “Our research demonstrates that the use of leaky vaccines can promote the evolution of nastier ‘hot’ viral strains that put unvaccinated individuals at greater risk.”

The theory tested by the research team was highly controversial when it first was proposed over a decade ago. The team’s experiments now show, for the first time, that the modern leaky vaccines, widely used in the agricultural production of poultry, can have precisely the effect on evolution of more-virulent strains of the virus that the controversial theory predicted.

Marek’s disease used to be a minor disease that did not do much harm to chickens in the 1950s, but the virulence of the virus has evolved and today it even is capable of killing all the unvaccinated birds in poultry flocks, sometimes within 10 days. “Even though the Marek’s disease virus is much nastier now than it was in the 1950s, it is becoming increasingly rare and now it causes relatively minor problems in the poultry industry because almost every chicken in agricultural production worldwide is vaccinated against the disease,” Read said. If you can vaccinate all the individuals in a population against a virus, it does not matter if the virus has become super virulent so long as the vaccine continues to be effective.”

The virus for Marek’s disease is very virulent, but the virus causing avian influenza can be even worse. “The most-virulent strain of avian influenza now decimating poultry flocks worldwide can kill unvaccinated birds in just under three days,” Read said. The vaccine against avian influenza is a leaky vaccine, according to Read. “In the United States and Europe, the birds that get avian influenza are culled, so no further evolution of the virus is possible,” Read said. “But instead of controlling the disease by culling infected birds, farmers in Southeast Asia use vaccines that leak — so evolution of the avian influenza virus toward greater virulence could happen.”

The research has implications for human health, as well. The World Health Organization recently reported laboratory-confirmed cases in China of human infection with the avian influenza virus, including a number of deaths. “We humans never have experienced any contagious disease that kills as many unvaccinated hosts as these poultry viruses can, but we now are entering an era when we are starting to develop next-generation vaccines that are leaky because they are for diseases that do not do a good job of producing strong natural immunity — diseases like HIV and malaria,” Read said.

“Vaccines for human diseases are the least-expensive, most-effective public-health interventions we ever have had,” Read said. “But the concern now is about the next-generation vaccines. If the next-generation vaccines are leaky, they could drive the evolution of more-virulent strains of the virus.” He said it is critical now to determine as quickly as possible that the Ebola vaccines that now are in clinical trials are not leaky — that they completely prevent the transmission of the Ebola virus among people. “We do not want the evolution of viral diseases as deadly as Ebola evolving in the direction that our research has demonstrated is possible with less-than-perfect, leaky vaccines,” Read said.

The researchers recommend rigorous testing and vigilant monitoring of next-generation vaccines to prevent the runaway evolution of more-virulent strains of viruses that their research has confirmed can occur with leaky vaccines. “If some day we have a malaria vaccine or an HIV vaccine, of course we should use those vaccines, but we would be in significant danger if those vaccines turned out to be leaky and we had not developed effective ways to eradicate any strains that might become more virulent,” Read said.

Read also recommends vaccination for individual protection. “When evolution toward more-virulent virus strains takes place as a result of vaccination practices, it is the unvaccinated individuals who are at the greatest risk. Those who are not vaccinated will be exposed, without any protection, to the hottest strains of a virus. Our research provides strong evidence for the importance of getting vaccinated.” Science Daily Original we page at Science Daily


Vaccine to protect global communities from malaria under development

A University of Oklahoma professor studying malaria mosquito interaction has discovered a new mosquito protein for the development of a new vaccine that is expected to stop the spread of the disease in areas where it is considered endemic. Malaria is transmitted by mosquitoes, and it infects millions of people in Africa, Asia and South America every year, causing a global health crisis. In addition to the local populations, U.S. military personnel stationed in these areas and travelers to these malaria-prone areas are at risk of becoming infected.

Jun Li, assistant professor in the Department of Chemistry and Biochemistry, OU College of Arts of Sciences, will travel to Kenya this July to test the newly-developed vaccine in the field. Since mosquitoes are essential for malaria transmission, Li and his colleagues from the OU Norman campus, the OU Health Sciences Center and John Hopkins University have found that an antibody used against a key mosquito protein inhibited malaria parasite invasion in mosquitoes. The antibody blocks the malaria parasite from the protein, which is needed for the parasite to invade mosquitoes.

“Vaccination with this mosquito protein would stop the spread of malaria in communities where it is most needed,” says Li. “The vaccine should protect an entire community by keeping mosquitoes from transmitting the disease, and it has the potential to dramatically reduce the number of malaria cases around the world.”

According to the World Health Organization, there were about 198 million cases of malaria in 2013 and an estimated 584,000 deaths. Most deaths occur among children living in Africa, where a child dies every minute from malaria. Approximately half of the world’s population is at risk of malaria. In 2014, 97 countries and territories had ongoing malaria transmission.

A technical paper on this research is published in the July 3, 2015, issue of the Journal of Biological Chemistry Science Daily  Original web page at Science Daily


Vaccines developed for H5N1, H7N9 avian influenza strains

Researchers have developed vaccines for H5N1 and H7N9, two new strains of avian influenza that can be transmitted from poultry to humans. The strains have led to the culling of millions of commercial chickens and turkeys as well as the death of hundreds of people. Wenjun Ma, assistant professor of diagnostic medicine and pathobiology at Kansas State University, left, and Jürgen Richt, Regents distinguished professor of veterinary medicine and director of the U.S. Department of Homeland Security’s Center of Excellence for Emerging and Zoonotic Animal Diseases, have developed vaccines for H5N1 and H7N9, two emerging strains of avian influenza. The strains are zoonotic and can be transmitted from chickens to pigs and humans.

A recent study with Kansas State University researchers details vaccine development for two new strains of avian influenza that can be transmitted from poultry to humans. The strains have led to the culling of millions of commercial chickens and turkeys as well as the death of hundreds of people. The new vaccine development method is expected to help researchers make vaccines for emerging strains of avian influenza more quickly. This could reduce the number and intensity of large-scale outbreaks at poultry farms as well as curb human transmission.

It also may lead to new influenza vaccines for pigs, and novel vaccines for sheep and other livestock, said Jürgen Richt, Regents distinguished professor of veterinary medicine and director of the U.S. Department of Homeland Security’s Center of Excellence for Emerging and Zoonotic Animal Diseases. Richt and his colleagues focused on the avian influenza virus subtype H5N1, a new strain most active in Indonesia, Egypt and other Southeast Asian and North African countries. H5N1 also has been documented in wild birds in the U.S., though in fewer numbers.

“H5N1 is a zoonotic pathogen, which means that it is transmitted from chickens to humans,” Richt said. “So far it has infected more than 700 people worldwide and has killed about 60 percent of them. Unfortunately, it has a pretty high mortality rate.” Researchers developed a vaccine for H5N1 by combining two viruses. A vaccine strain of the Newcastle disease virus, a virus that naturally affects poultry, was cloned and a small section of the H5N1 virus was transplanted into the Newcastle disease virus vaccine, creating a recombinant virus. Tests showed that the new recombinant virus vaccinated chickens against both Newcastle disease virus and H5N1.

Researchers also looked at the avian flu subtype H7N9, an emerging zoonotic strain that has been circulating in China since 2013. China has reported about 650 cases in humans and Canada has reported two cases in people returning from China. About 230 people have died from H7N9. “In Southeast Asia there are a lot of markets that sell live birds that people can buy and prepare at home,” Richt said. “In contrast to the H5N1 virus that kills the majority of chickens in three to five days, chickens infected with the H7N9 virus do not show clinical signs of sickness. That means you could buy a bird that looks perfectly healthy but could be infected. If an infected bird is prepared for consumption, there is a high chance you could get sick, and about 1 in 3 infected people die.”

Using the same method for developing the H5N1 vaccine, researchers inserted a small section of the H7N9 virus into the Newcastle disease virus vaccine. Chickens given this recombinant vaccine were protected against the Newcastle disease virus and H7N9. “We believe this Newcastle disease virus concept works very well for poultry because you kill two birds with one stone, metaphorically speaking,” Richt said. “You use only one vector to vaccinate and protect against a selected virus strain of avian influenza.” Using the Newcastle disease virus for vaccine development may extend beyond poultry to pigs, cattle and sheep, Richt said.  Science Daily  Original web page at Science Daily


* Ebola whole virus vaccine shown effective, safe in primates

The vaccine, described today (March 26, 2015) in the journal Science, was developed by a group led by Yoshihiro Kawaoka, a University of Wisconsin-Madison expert on avian influenza, Ebola and other viruses of medical importance. It differs from other Ebola vaccines because as an inactivated whole virus vaccine, it primes the host immune system with the full complement of Ebola viral proteins and genes, potentially conferring greater protection. “In terms of efficacy, this affords excellent protection,” explains Kawaoka, a professor of pathobiological sciences in the UW-Madison School of Veterinary Medicine and who also holds a faculty appointment at the University of Tokyo. “It is also a very safe vaccine.” The vaccine was constructed on an experimental platform first devised in 2008 by Peter Halfmann, a research scientist in Kawaoka’s lab. The system allows researchers to safely work with the virus thanks to the deletion of a key gene known as VP30, which the Ebola virus uses to make a protein required for it to reproduce in host cells. Ebola virus has only eight genes and, like most viruses, depends on the molecular machinery of host cells to grow and become infectious.

By engineering monkey kidney cells to express the VP30 protein, the virus can be safely studied in the lab and be used as a basis for devising countermeasures like a whole virus vaccine. The vaccine reported by Kawaoka and his colleagues was additionally chemically inactivated using hydrogen peroxide, according to the new Science report. Ebola first emerged in 1976 in Sudan and Zaire. The current outbreak in West Africa has so far claimed more than 10,000 lives. There are no proven treatments or vaccines, although several vaccine platforms have been devised in recent years, four of which recently advanced to the clinical trial stage in humans. The new vaccine reported by Kawaoka has not been tested in people. However, the successful tests in nonhuman primates conducted at the National Institutes of Health (NIH) Rocky Mountain Laboratories, a biosafety level 4 facility in Hamilton, Montana, may prompt further tests and possibly clinical trials of the new vaccine. The work at Rocky Mountain Laboratories was conducted in collaboration with a group led by Heinz Feldmann of NIH. Those studies were conducted with cynomolgus macaques, which are very susceptible to Ebola. “It’s the best model,” Kawaoka says. “If you get protection with this model, it’s working.”  Science Daily  Original web page at Science Daily


Tumour mutations harnessed to build cancer vaccine

Personalized vaccines could provide new options to treat cancers driven by multiple genetic mutations. Vaccines made from mutated proteins found in tumours have bolstered immune responses to cancer in a small clinical trial. The results, published on 2 April in Science, are the latest from mounting efforts to generate personalized cancer therapies. In this case, three people with melanoma received vaccines designed to alert the immune system to mutated proteins found in their tumours.

It is too soon to say whether the resulting immune response will be enough to rein in tumour growth, but the trial is a crucial proof of concept, says Ton Schumacher, a cancer researcher at the Netherlands Cancer Institute in Amsterdam. We don’t really know how strong an immune response has to be to be clinically meaningful,” he says. “Nevertheless, it’s an important step.” Cancer is a genetic disease, driven by mutations that lift the brakes on cell proliferation. But the mutated proteins produced by cancerous cells can serve as a siren call to immune cells, signalling the presence of a cell that has become, in a sense, ‘foreign’. Unfortunately, many of these calls are never heard. Some tumours suppress nearby immune responses, and mutated tumour proteins may not be expressed at high enough levels to rally immune cells. Researchers have long dreamed of using those mutated proteins to generate a vaccine, says immunologist Beatriz Carreno of Washington University in St. Louis, Missouri, but lacked the technological wherewithal to do so.

The advent of cancer-genome sequencing and an improved understanding of the immune system have converged to make that approach possible. Last year, two groups, showed that such vaccines can work in mice. Carreno and her colleagues have now taken the approach into humans. The researchers sequenced the tumour genomes in samples taken from three people with melanoma and catalogued the mutated proteins in each sample. They then chose seven protein fragments per patient for use in the vaccine. White blood cells were taken from each patient and cultured in the laboratory to generate immune cells called dendritic cells. These cells were then exposed to the protein fragments, allowed to mature in the laboratory and then infused into the patients. By then, the dendritic cells had taken up the protein fragments, and were able to present them to immune cells in the body. The result: immune cells trained to target the mutated proteins produced by the tumour. Such immune cells were evident in the patients’ blood two weeks after vaccination.

Researchers have tried to develop cancer vaccines for decades, but early signs of success have tended to give way to disappointment in larger clinical trials. The same could hold true in this case, but there is cause to be optimistic, says Schumacher. Past vaccines were made with proteins that are also found in normal cells, but were simply more abundant in tumours. The immune system is trained to tolerate such proteins, so responses to the proteins remained weak even after vaccination. In this case, the proteins are not found in normal cells, and therefore should elicit a stronger response, he notes. Carreno adds that previous vaccines also generally involved only a single cancer-associated protein. Her vaccines are based on seven.

Carreno thinks that the approach could also work in other cancers that contain a lot of mutations, such as lung, colon and bladder tumours. And although the procedure is complicated, pharmaceutical companies have shown that they are willing to take on complex, personalized cancer therapies. “The pipeline for identifying mutated proteins will get more efficient with time,” Carreno says. “This therapy is no more complicated than the other therapies that are now being considered.”

Nature doi:10.1038/nature.2015.17250 Nature Original web page at Nature


Low vaccination rates likely fuel the 2015 measles outbreak, calculations show

Inadequate vaccine coverage is likely a driving force behind the ongoing Disneyland measles outbreak, according to calculations by a research team at Boston Children’s Hospital. Their report, based on epidemiological data and published online by JAMA Pediatrics, indicates that vaccine coverage among the exposed populations is far below that necessary to keep the virus in check, and is the first to positively link measles vaccination rates and the ongoing outbreak. By examining case numbers reported by the California Department of Public Health and current and historical case data captured by the HealthMap disease surveillance system, the researchers–led by Maimuna Majumder, MPH, and John Brownstein, PhD, of Boston Children’s Informatics Program–estimate that the measles vaccination rate among the case clusters in California, Arizona and Illinois is between 50 and 86 percent, far below the 96 to 99 percent necessary to create a herd immunity effect.

Measles is highly contagious. It’s estimated that an infected individual in a population fully susceptible to measles will spread the virus to between 11 and 18 additional people. This number is called the virus’s basic reproduction rate, or R0. In a population where at least some individuals are immune to measles, the virus spreads from person to person more slowly. The rate of spread in an immune population is called the virus’s effective reproduction rate, or RE.

Using case data, R0 and measles’ serial interval (the length of time for each successive wave of transmission to follow the one before), Majumder and Brownstein calculated that the virus’s RE in the Disneyland outbreak is between 3.2 and 5.8. From there, the pair calculated their vaccination estimate. The researchers are quick to note that their estimate does not reflect vaccination across the United States, the state of California or even among the population of Disneyland visitors at the outbreak’s start. Rather, it reflects the vaccination rate among the exposed populations in each cluster of cases linked to the outbreak so far. “It’s as though you took everyone exposed to measles in the areas with case clusters, put them in a room and measured the level of vaccine coverage in that aggregate population,” says Majumder.

Using the same data sources, the HealthMap team has separately released an interactive model illustrating how differing rates of vaccine coverage could affect the growth of a measles outbreak over time. The model, available at, puts the effects of vaccination into stark relief. If a population is fully vaccinated against the virus, the model predicts that one case of measles will give rise to only two additional cases over 70 days. By contrast, if only 60 percent of a population is vaccinated, more than 2,800 cases will occur over the same time period. “Our data tell us a very straightforward story–that the way to stop this and future measles outbreaks is through vaccination,” says Brownstein, a digital epidemiologist and co-founder of HealthMap and VaccineFinder, an online service that allows users to search for locations offering a variety of vaccinations, including the MMR vaccine that protects against measles. “The fundamental reason why we’re seeing the number of cases we are is inadequate vaccine coverage among the exposed. “We hope these data encourage families to ensure they and their loved ones are vaccinated,” he continues, “and help local public health officials in their efforts to control this outbreak.”  Science Daily  Original web page at Science Daily


Opinions on vaccinations heavily influenced by online comments

With measles and other diseases once thought eradicated making a comeback in the United States, healthcare websites are on the spot to educate consumers about important health risks. Washington State University researchers say that people may be influenced more by online comments than by credible public service announcements (PSAs). Writing in the Journal of Advertising, WSU marketing researchers Ioannis Kareklas, Darrel Muehling and TJ Weber are the first to investigate how Internet comments from individuals whose expertise is unknown impact the way people feel about vaccines. Their study, “Reexamining Health Messages in the Digital Age: A Fresh Look at Source Credibility Effects,” comes after a recent outbreak of measles linked to Disneyland parks in California has affected at least 100 people in the United States and Mexico. “In the context of health advertising, few issues have concerned advertisers, researchers and consumers — especially those with young children — more than recent trends in vaccination attitudes and behaviors,” wrote Kareklas and colleagues. Kareklas, Muehling and Weber conducted two experiments. In the first, they showed 129 participants two made-up PSAs. Participants were led to believe that the pro-vaccination PSA was sponsored by the U.S. Centers for Disease Control and Prevention (CDC), while the anti-vaccination PSA was sponsored by the National Vaccine Information Council (NVIC). Both PSAs were designed to look like they appeared on each organization’s respective website to enhance validity. The PSAs were followed by comments from fictitious online commenters who either expressed pro- or anti-vaccination viewpoints. Participants weren’t told anything about who the commenters were, and unisex names were used to avoid potential gender biases. After looking at the PSAs and comments, people responded to questionnaires that rated their likelihood to vaccinate themselves and their family members, as well as their opinions about vaccination. Results showed participants were equally persuaded by the PSAs and the online comments. “That kind of blew us away,” said Kareklas. “People were trusting the random online commenters just as much as the PSA itself.” In the second experiment, participants were told the fictitious commenters were an English literature student, a lobbyist specializing in healthcare issues and a medical doctor specializing in infectious diseases and vaccinology. The researchers determined that participants found the doctor’s comments to be more impactful than the PSAs. “We found that when both the sponsor of the PSA and the relevant expertise of the online commenters were identified, the impact of these comments on participants’ attitudes and behavioral intentions was greater than the impact of the PSA and its associated credibility,” the researchers wrote. The study provides some valuable insight into why the anti-vaccination movement has been so persistent. As the paper points out, researchers have long known that people take word-of-mouth communications — both electronic and in person — more seriously than they do advertisements. Kareklas cited three instances in which popular press including Science, the Huffington Post and the Chicago Sun Times have banned anonymous online comments because they feel people are discrediting proven science. “We don’t subscribe to the practice of taking down comments,” he said, “because managers would also lose credibility if they only posted positive comments.” The researchers suggest that social advertisers must first be vigilant that their attempts to persuade are not perceived by readers as being manipulative or disingenuous. Health websites should include opposing viewpoints where relevant, but should also ensure that supportive comments are abundant, easily accessible and supported by research evidence. “It would be advisable for some supportive comments from noted experts to be highlighted on health websites,” they said. They recommended that advertisers clearly identify the expertise of the commenter — for example, a medical doctor specializing in a related field of medicine. Most important, the researchers said social advertisers must strive to develop online media strategies that encourage “credible online exchanges where innovative thinking facilitates collaborative problem solving and results in improving customer welfare for all parties involved.”  Science Daily  Original web page at Science Daily


Developing vaccines for insect-borne viruses

Vaccines developed using proteins rather than live viruses can help protect animals and subsequently humans from insect-borne viruses, according to Alan Young, chief scientific officer for Medgene Labs, an animal health company that develops therapeutics and diagnostics, including vaccines. “Platform technologies — that is where our niche is,” said Young, who is also a veterinary science professor at South Dakota State University. Medgene uses advances in molecular biology and technologies licensed from the university.

The company’s initial vaccine formulation targets Rift Valley Fever, found in Africa and the Arabian Peninsula. The viral disease is particularly devastating to sheep, with a mortality rate of 90 percent in lambs and 10 percent in adult sheep. The virus affects cattle, camels and goats similarly, but to a lesser extent. It can be spread to humans in the same manner as animals — through the bite of an infected mosquito. Of the vaccines available, the one produced from a live virus can result in spontaneous abortions in pregnant ewes and the one from an inactivated virus does not provide long-term immunity, according to the Centers for Disease Control and Prevention. Medgene is developing a vaccine to alleviate both problems. Four ewes in an experimental group lambed after being vaccinated, according to director of lab operations, Jessica Zweibahmer. The next step will be to test the lambs for antibodies to see if the immunity crossed over from mother to fetus. Young explained that using proteins rather than live agents to produce an immune reaction significantly reduces the chance of side effects. That makes Medgene’s vaccines both safe and effective.

“We approach vaccine targets from a virus family perspective,” Young said. For instance, what works for Rift Valley Fever can then be applied to Heartland virus, which is in the same family, and a vaccine for Porcine Epidemic Diarrhea virus can be expanded to Porcine Delta Coronavirus. Recent changes in the way regulatory agencies license vaccines could reduce the path to licensing a vaccine to as little as 12 months, according to Young. “We have a well-developed expression technology to produce these proteins,” Young said. “Inserting a different section in the sequence will allow us to produce a new vaccine more quickly.” Young credits company co-founder South Dakota Innovation Partners for providing the support his business needs. Partnership agreements secured by SDIP provide a pathway for worldwide distribution. Science Daily Original web page at Science Daily


Beating the clock: researchers develop new treatment for rabies

Successfully treating rabies can be a race against the clock. Those who suffer a bite from a rabid animal have a brief window of time to seek medical help before the virus takes root in the central nervous system, at which point the disease is almost invariably fatal. Now, researchers at the University of Georgia have successfully tested a new treatment on mice that cures the disease even after the virus has spread to the brain. They published their findings recently in the Journal of Virology. “Basically, the best way to deal with rabies right now is simple: Don’t get rabies,” said study co-author Biao He, a professor of infectious diseases in the UGA College of Veterinary Medicine. “We have vaccines that can prevent the disease, and we use the same vaccine as a kind of treatment after a bite, but it only works if the virus hasn’t progressed too far. “Our team has developed a new vaccine that rescues mice much longer after infection than what was traditionally thought possible.”

In their mouse experiments, the animals were exposed to a strain of the rabies virus that generally reaches the brain of infected mice within three days. By day six, mice begin to exhibit the telltale physical symptoms that indicate the infection has become fatal. However, 50 percent of mice treated with the new vaccine were saved, even after the onset of physical symptoms on day six. “This is the most effective treatment we have seen reported in the scientific literature,” He said. “If we can improve these results and translate them to humans, we may have found one of the first useful treatments for advanced rabies infection.” He and his colleagues developed their vaccine by inserting a protein from the rabies virus into another virus known as parainfluenza virus 5, or PIV5, which is thought to contribute to upper respiratory infections in dogs but is completely harmless to humans. PIV5 acts as a delivery vehicle that carries the rabies protein to the immune system so it may create the antibodies necessary to fight off the virus. “This is only the beginning of our work,” He said. “While these preliminary results are very exciting, we are confident that we can combine this new vaccine with other therapies to boost survival rates even higher and rescue animals even when symptoms are severe.”

Apart from being very effective in saving the infected mice, the researchers emphasized that their vaccine is much safer when compared to the best current treatment in mice, which uses a weakened version of the rabies virus. “It doesn’t matter how we weaken the current vaccine, the virus inside it is still rabies,” said study co-author Zhen Fu, a professor of pathology in the college. “That is not a concern with our PIV5 vaccine.” The researchers will continue to perfect their vaccine’s design and hope to move into more advanced animal trials soon. “There is an urgent need in many parts of the world for a better rabies treatment, and we think this technology may serve as an excellent platform,” He said. “Ultimately, we just want to try to save more lives.” Science Daily Original web page at Science Daily