Kat Kelley

Reducing unnecessary antibiotic use is widely considered a priority action in combating the spread of antimicrobial resistance. In the United States, one-third of antibiotic prescriptions are unnecessary and each year, there are 27 million gratuitous prescriptions for respiratory infections alone. Rapid, point-of-care diagnostics that can discern if an infection is bacterial could significantly reduce this practice, preventing antibiotic prescriptions for viral, parasitic, or fungal infections. There are now several tests in the pipeline which evaluate the level of C-reactive protein (CRP) in the bloodstream, a molecule associated with inflammation. CRP levels increase significantly in response to bacterial infections, but only slightly in response to viral infections. Not only have several of these tests proven reliable, but new research conducted by the Oxford University Clinical Research Unit in Vietnam indicates that such a test can successfully decrease antibiotic prescriptions for respiratory infections in low-resource settings. The study monitored antibiotic use for 2,000 patients at ten primary health centers, and use of the test reduced prescriptions from 78 to 64 percent, without impacting clinical recovery or patient satisfaction rates. Scientists have identified a compound that shows promise in treating three different parasitic diseases—Chagas disease, sleeping sickness, and leishmaniasis—that effect 20 million people and result in 50,000 deaths each year. The three diseases are caused by distinct parasites and transmitted by different vectors. Chagas disease results in cardiac complications, sleeping sickness causes neurological symptoms, and leishmaniasis manifests as skin sores and liver and/or spleen damage. Existing treatments are toxic, expensive, and difficult to administer in low-resource settings. The compound—GNF6702—was developed by pharmaceutical company Novartis and discovered after screening 3 million molecules in the company’s compound library. The molecule was then modified, resulting in a drug with 20 times the original potency. The compound targets proteasome—which breaks down waste—in all three parasites, but does not have the same effect in mammal cells. The drug has proven effective in mice, and will undergo additional safety tests before the initiation of human clinical trials.  The US Agency for International Development (USAID) announced last week the initial winners of its Combating Zika and Future Threats Grand Challenge, through which the agency will be providing more than US$15 million for the development and introduction of 21 innovative tools and interventions. In just two months, USAID received and reviewed nearly 900 applications, addressing various parts of outbreak prevention, detection, and control, including vector control, personal and household protection, vector and disease surveillance, community engagement, and diagnostic innovations. The winners include an electric force field to repel mosquitoes; a flip phone–based app that can distinguish between mosquito species, enabling crowdsourced vector surveillance; insecticide-treated sandals; and a human-scented mosquito trap. The agency will announce additional winners in the next month and will invest up to $30 million total.

Researchers at the University of Pennsylvania have designed a placenta-on-a-chip: a small device that mimics the placental barrier, enabling scientists to study the transport of molecules from mother to fetus. The silicone device contains a permeable membrane surrounded by endothelial and trophoblast cells, which are found in fetal blood vessels and where the placenta meets the maternal blood supply, respectively. The model imitates the development of the placenta throughout pregnancy, as trophoblast cells merge and as the barrier becomes thinner. Previously, donated placental tissue has been used in research, however samples are scarce and only viable for a few hours after delivery. The team completed an initial, successful test of the device by comparing the transfer of glucose across the placental barrier in both donated tissue and the placenta-on-a-chip. As testing continues, plans are underway to use the device in studies on preterm birth. The secret to fighting methicillin-resistant Staphylococcus aureus (MRSA) could be an antibiotic produced by the microbes inhabiting the human nose. MRSA is a dangerous bacterium, resistant to several leading antibiotics, that causes staph infections, sepsis, and pneumonia, resulting in 20,000 deaths annually. Researchers at the University of Tübingen in Germany cultured the bacteria in snot samples from 37 healthy individuals, hoping to understand why vulnerability to staph infections varies from person to person. Next, they placed S. aureus alongside the different bacteria, and identified another species of staph— Staphylococcus lugdunensis—that successfully combatted S. aureus. The team then collected snot samples from 187 hospital patients, and with just one exception, found either S. aureus or S. lugdunensis in every sample, suggesting that the two cannot flourish in unison. The key compound—lugdunin—successfully treated staph infections in mice and, after leaving the two bacteria in petri dishes for a month, S. aureus was unable to develop resistance to S. lugdunensis. An ongoing outbreak of yellow fever in Angola and the Democratic Republic of the Congo has resulted in more than 5,000 cases and nearly 450 deaths. The existing vaccine against the virus is extremely effective, but is not recommended for pregnant women and those over 60 years of age. The vaccine takes a year to produce and the limited global stockpile has already been depleted twice this year. Last week, the US National Institutes of Health initiated a phase 1 clinical trial to test the safety and tolerability of an experimental yellow fever vaccine. The vaccine candidate, developed by Danish company Bavarian Nordic, uses a weakened version of the Modified Vaccinia Ankara virus as a vector to transport genes from the yellow fever virus. This delivery platform has been used in vaccinating more than 7,600 individuals, 1,000 of them immunocompromised. The trial will enroll 90 healthy volunteers, 15 of whom will receive the existing, approved yellow fever vaccine, and 75 of whom will receive one or two doses of the experimental vaccine or a placebo, with or without a booster.

Scientists have long known that the composition of the vaginal microbiome—the bacterial environment in the vagina—can be hostile or even toxic to pathogens and sperm. Now, research conducted by the Centre for the AIDS Programme of Research in South Africa (CAPRISA) suggests that the presence of Prevotella bivia bacteria can significantly increase a woman’s risk for contracting HIV, while the Gardnerella vaginalis bacteria can interfere with the preventative antiretroviral drug tenofovir. The team at CAPRISA sequenced the vaginal microbiomes of 120 women in South Africa, and reported that presence of P. bivia was associated with a 20-fold higher risk for HIV and AIDS. Infection with P. bivia results in an inflammatory response, in which immune cells—including CD4 T cells—are sent to the vaginal surface. CD4 T cells are the main target of the HIV virus, and the influx makes it much easier for the virus to take hold in the body. The team also dug into why the efficacy of tenofovir—which both treats and prevents HIV—varies significantly in women. CAPRISA had previously tested an HIV prevention gel containing tenofovir in women, and had frozen and stored vaginal microbiome samples from participants. The samples revealed a correlation between high levels of G. vaginalis and HIV infection, prompting the team to study the two in the lab. Within 24 hours, the bacteria was able to completely consume the antiretroviral, halting any protection the drug may offer. A vaccine candidate against chlamydia proved promising in animal trials, resulting in a lower presence of the bacteria and reducing damage to reproductive health organs in vaccinated versus unvaccinated mice. Chlamydia is one of the most common sexually transmitted infections (STIs)—with an estimated 131 million new cases each year—and can be cured with antibiotics. While many cases are initially asymptomatic, the disease can cause pelvic inflammatory disorder and infertility if left untreated. The vaccine, developed by researchers at McMaster University in Ontario, contains three different proteins found on the bacterium. The team reported a 95 percent decrease in chlamydial shedding—an indication of the infection spreading throughout the body—and an 87.5 percent decrease in hydrosalpinx, which can damage the fallopian tubes. The team will continue testing the vaccine in varying formulations and in other animal models before initiating human clinical trials. Earlier this year, the International Partnership for Microbicides (IPM) announced the results of two large phase 3 clinical trials—The Ring Study and ASPIRE—demonstrating that a monthly vaginal ring containing the antiretroviral dapivirine could reduce HIV risk in women by 31 and 27 percent, respectively. However, new findings suggest that when used consistently, the ring can reduce HIV risk by 56 percent, and in a subset of women who used the ring most effectively, the ring slashed HIV risk by 75 percent. The dapivirine ring, developed by IPM, is the only long-acting, female-initiated HIV prevention method to have successfully completed large efficacy trials. IPM has initiated two open-label studies of the dapivirine ring and is seeking regulatory approval for the ring.

Earlier this year, the World Health Organization (WHO) declared the outbreak of Zika in Latin America a Public Health Emergency of International Concern. The virus, spread by the Aedes aegypti mosquito, was once considered innocuous, causing a mild illness and lasting for only a handful of days. However, the virus has since been linked to devastating birth defects and neurological complications and has spread to more than 60 countries. The virus’s virulence took the research community by storm: although it was discovered in 1947, only 25 scientific papers were published on the topic prior to the current outbreak. As the scientific community learns more about the virus and the disease, the need for tools to prevent, detect, and treat it has become undeniable. On February 22, US President Barack Obama submitted a request to Congress for US$1.9 billion in emergency funding to combat the virus, a critical move, as the US government is unrivaled as the largest funder of global health research and development (R&D). However, 146 days later, Congress has yet to reach a deal, and the US agencies leading the fight against Zika are running out of money. In the meantime, these agencies have made impressive strides in advancing Zika R&D using limited funding and leveraging cross-sector partnerships. An unprecedented number of private-sector partners have also entered the hunt for Zika countermeasures, building out a robust pipeline in record time. Below, we highlight the most promising vaccine, drug, and diagnostic candidates as well as vector control approaches. Vaccines There are currently more than 35 Zika vaccine projects underway, and at least 3 have completed successful animal trials. Inovio Pharmaceuticals and GeneOne Life Sciences partnered to develop a DNA-based vaccine, using a unique delivery approach—electroporation—in which a device is applied to the injection site, sending out electrical pulses that enhance the vaccine’s ability to enter human cells. The vaccine successfully prompted an immune response, including the production of protective antibodies, in both mice and monkeys. In late June, the experimental vaccine became the first to be approved for human clinical trials by the US Food and Drug Administration (FDA). The phase 1 trial, which will enroll 40 healthy adults, is intended to evaluate the safety and tolerability; however, the team will also monitor its ability to induce an immune response. Meanwhile, two more vaccine candidates have proven effective in mice. The candidates include a DNA-based vaccine and one composed of an inactivated version of the Zika virus, the first supported by the US National Institutes of Health (NIH) and the second developed by the US Walter Reed Army Institute of Research. The latter will be tested in phase 1 clinical trials by the US National Institute of Allergy and Infectious Diseases and then transferred to French pharmaceutical company Sanofi for further clinical development. Sanofi is also working on a vaccine of its own; however, it won’t enter clinical trials until 2017. After several months of feasibility studies, British pharmaceutical company GlaxoSmithKline has announced that it will be partnering with the NIH to test its RNA-based vaccine in animals. To date, no DNA or RNA vaccines have been approved for use in humans, although they are often called the future of vaccines. Drugs Due to the dearth of knowledge about the virus and the difficulty of conducting clinical trials and using novel drugs in pregnant women—a key target population for Zika control—the WHO has stated, “It is unlikely at this stage that therapeutics will constitute a priority activity.” However, efforts are underway, both to discover novel treatments and to repurpose existing medicines. Australian biotech company Biotron announced recently that two compounds in their library have proven effective against Zika in test tubes. They will continue to conduct laboratory tests to better assess the safety and efficacy of the compounds in humans. Researchers at the US National Center for Advancing Translational Sciences are screening their compound library—with half a million entities— and have identified a novel drug, which is safe for use in humans and currently in clinical trials for cancer, that prevented the virus from killing progenitor cells, which play a critical role in the neurological system and fetal development. Researchers at the University of California, San Diego are embarking on an ambitious study to virtually screen more than 20 million compounds against the virus. The program—OpenZika—uses a research collaboration platform to harness the power of volunteers’ computers and smartphones. Participants download the software, and when their computer or phone is inactive, it runs calculations to predict how a compound will interact with the virus in the lab. Researchers are also looking at repurposing existing drugs as Zika treatments. Chloroquine—which both prevents and treats malaria—has successfully protected against Zika virus in vitro. A team at Katholieke Universiteit Leuven has identified an experimental treatment for hepatitis C that delayed the manifestation of Zika-related symptoms in mice. And scientists at the University of California, San Francisco reported that the antibiotic azithromycin—which has long been used in pregnant women—blocked the virus from multiplying in petri dishes. Diagnostics As of March, more than 30 diagnostics for the virus were under development, and the FDA has sanctioned the use of five tests—four that detect current infection and one to assess previous exposure—under its Emergency Use Authorization program. However, rapid, point-of-care diagnostics are desperately needed. Eighty percent of cases are asymptomatic, and initial symptoms—fever, rash, joint pain—are nonspecific. Thus, early and accurate diagnosis is critical to ensure appropriate treatment. A team of Harvard University and Massachusetts Institute of Technology researchers have designed a paper-based test that can diagnose cases within a few hours. The device is appropriate for low-resource settings: it’s cheap, it can be stored or shipped at room temperature, and the results are easy to interpret. The tool contains miniscule sensors that change color in the presence of a specific genetic sequence. To ensure accurate detection of the virus, the team developed sensors that can detect 24 different genetic sequences found in the Zika genome. The device has been tested using samples from infected monkeys and has proven to be effective at detecting even low quantities of the virus. Although the results are easy to read—a positive sample turns the strip purple—the team has also created a simple electronic reader that determines the quantity of the virus in the sample. Vector Control As vaccines, drugs, and diagnostics against the virus inch their way through the R&D pipeline, health officials are ramping up vector control efforts against the Aedes aegypti mosquito. New techniques are also underway, and the FDA is currently accepting public comment on a proposal to expand testing of genetically engineered mosquitoes. The mosquitoes mate with the local population, resulting in offspring that die before reaching adulthood and are consequently not able to spread diseases. A trial of the mosquitoes in Brazil led to an 82 percent decrease in the Aedes aegypti population in just nine months. Scientists are using innocuous bacteria and fungi to combat the spread of Zika. Male mosquitoes infected with the Wolbachia bacteria do not produce viable offspring, and tests across the United States have reduced the population of the closely related Aedes albopictus mosquito by an estimated 70 percent. Meanwhile, the Metarhizium brunneum fungus is used as a natural pesticide, killing mosquito larvae. Meanwhile, in North Hempstead, New York, bats have been enlisted in the fight against Zika. The city is building and hanging bat houses in parks to attract the animals, as they can eat more than 1,000 mosquitoes in an hour.

New research suggests that viral hepatitis is a leading infectious disease killer, resulting in 1.45 million deaths in 2013, more than HIV and AIDS and just short of tuberculosis, which killed 1.2 and 1.5 million in 2014, respectively. Five viruses—hepatitis A, B, C, D, and E—cause the disease, and a new World Health Organization (WHO) strategy seeks to reduce new cases of hepatitis B and C—responsible for the most deaths worldwide—by 30 percent over the next four years. Vaccines are available against hepatitis A and B, and new treatments, including cures, against hepatitis C are on the market and under development, although treatment costs remain prohibitive. The WHO is calling for expanded vaccination efforts and treatment coverage, as well as prevention of mother-to-child transmission of hepatitis B. The US National Institute of Allergy and Infectious Diseases is partnering with the Ministry of Health of Liberia and pharmaceutical company Gilead Sciences to test drug candidate GS-5734 in adult male survivors of Ebola, with the goal of eliminating the virus from the body. Since 2014, more than 28,000 cases of Ebola have been reported in West Africa, and survivors continue to experience a range of symptoms. The virus persists in the blood and semen, and at least one resurgence of the outbreak was due to transmission from a healthy survivor. The drug has proven safe for use in humans and effective against the virus in animals. During the six-month trial, 120 adult male survivors will receive either the drug candidate or a placebo, and will provide blood and semen samples, which will be examined for presence of the Ebola virus. Researchers at the University at Buffalo are developing a vaccine delivery system using innocuous strains of the Escherichia coli (E. coli) bacteria—many of which actually aid in human digestion. The team created a synthetic capsule with an E. coli core to deliver an investigational vaccine against pneumococcal disease. The vaccine effectively caused an immune response and protected against sepsis and pneumonia in mice. Both the vaccine and delivery system are being commercialized by biotech startup Abcombi Biosciences Inc., founded by Dr. Charles Jones, a co-author on the study and a former student of the study’s lead author, Dr. Blaine Pfeifer, a professor of Chemical and Biological Engineering at the University of Buffalo.

Just one case of yellow fever in an unvaccinated population is considered an outbreak, according to the World Health Organization (WHO). And now, an outbreak in Angola has spread to Kinshasa, a city of 12 million in the Democratic Republic of Congo. Health experts are calling it the worst yellow fever outbreak in Africa in decades. The outbreak in Angola has resulted in nearly 350 deaths, and unrelated outbreaks are ongoing in Uganda and Peru. Meanwhile, the WHO’s emergency stockpile of the yellow fever vaccine—the only available countermeasure against the virus—has been depleted twice this year, and is currently running low at only 6 million doses, raising concerns about global ability to respond to growing outbreaks.Background: The illness and impact of a historic virus Yellow fever is a mosquito-borne disease—spread by both the Aedes and Haemogogus species—found in both urban and rural settings. The disease is endemic in forty-seven countries across Africa and Latin America, and each year results in anywhere from 84,000 to 170,000 severe cases and 29,000 to 60,000 deaths. Many cases of yellow fever are asymptomatic, and when they manifest, initial symptoms are nonspecific: fever, fatigue, aches and pains, nausea, and vomiting. Fifteen percent of cases progress to a more severe illness  characterized by high fevers, liver and kidney damage, jaundice—thus the name yellow fever—and even hemorrhaging. Half of those who enter this toxic stage of infection die. While the yellow fever virus has plagued the world since the 17th Century, it was first isolated in 1900 by American pathologist Walter Reed, earning it the distinction of being the first human virus ever to be discovered. A safe and effective vaccine was first introduced in 1936; however, in the eight decades since, few new tools against the virus have been developed. Below, we break down the status of research and development (R&D) for vaccines, drugs, and diagnostics for yellow fever.Status of R&D and access to yellow fever countermeasures Vaccines Yellow Fever vaccine manufacturing facility Val de Reuil Sanofi Pasteur site, France (Photo: Sanofi Pasteur / Patrick Boulen)The yellow fever vaccine is effective, safe, and affordable. Just one dose provides lifetime protection from the virus for 99 percent of those vaccinated. However, the vaccine contains live virus, and in extremely rare cases, can result in illness. Since 2000, the price of the vaccine has risen 30 percent annually. However, this increase has not incentivized manufacturers to scale up production. There are only four manufacturers of the vaccine, and it’s notoriously difficult to produce. Consequently, the global demand for the vaccine surpasses availability by 42 percent. Yellow fever vaccine production relies on eggs from pathogen-free chickens flocks, which are hard to come by. The embryos are infected with the yellow fever virus, and after three to four days, the embryos are harvested under sterile conditions. Each egg can provide anywhere from 100 to 300 doses of the vaccine. The entire production process takes about one year. A vaccine candidate with an inactivated version of the virus completed successful phase 1 clinical trials in 2011. However, since GE Healthcare acquired the intellectual property for the vaccine in 2012, no additional clinical trials have been undertaken. Fortunately, last month PnuVax Incorporated entered into an agreement with GE Healthcare, under which PnuVax will advance the vaccine through clinical trials and will partner with GE Healthcare for manufacturing. In the meantime, the WHO is recommending that the vaccine be administered in fractional doses, using just one-fifth of the standard amount. Studies suggest that this approach still confers at least 12 months of protection from the virus, however, booster shots would be required to sustain immunity when a global shortage is no longer imminent. Additionally, fractional dosing has not been tested in children, raising concerns that this approach might not be sufficient for kids, whose immune responses, including to vaccines, are typically weaker. Drugs There are no specific therapies for yellow fever. Current treatment involves supportive care (i.e., addressing the symptoms). Animal studies suggest that the widely-used antiviral ribavirin and an active carboxamide drug reduce mortality in hamsters, and the molecule interferon-α, used in some cancer therapies, effectively treats the disease in monkeys. However, these treatments were only effective when administered within a few days of infection. Thus, even if they were to prove effective in humans, their application would be limited. The yellow fever virus incubates for three to four days in the body before symptoms appear, and as aforementioned, initial symptoms are nonspecific and easily confused with anything from malaria to dengue fever or leptospirosis to poisoning. Diagnostics As yellow fever is hard to distinguish from other illnesses based on initial symptoms alone, the development of rapid, point-of-care diagnostics is critically needed. Currently, cases can only be confirmed in laboratory settings. Diagnosis requires examining blood or serum for either the virus itself or antibodies against the virus. However, researchers at the Massachusetts Institutes of Technology are currently developing a paper-based diagnostic that simultaneously tests for Ebola, dengue fever, and yellow fever. The test is designed for use in low-resource settings, requiring no electricity or specialized lab equipment and the results are easy to interpret. Testing requires a small amount of blood, and colored nanoparticles appear—red for Ebola, orange for yellow fever, and green for dengue—based on the proteins in the blood. While this new tool is showing promise, it could be some years before testing is completed and regulatory approval is secured. With a limited pipeline of countermeasures against yellow fever, the global community is scrambling to ramp up vaccine production, expand vaccination coverage, and scale up vector control efforts. However, R&D for rapid, point-of care diagnostics; lifesaving treatments; and a safe, affordable, easy-to-produce vaccine is critical to combat this virus after a centuries-long battle.