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CDC microbiologist Brian Yoo prepares a panel of isolates. Photo: CDCThe threat of antibiotic resistance (AR) is a growing challenge around the world. Antibiotic-resistant germs—bacteria that no longer respond to the drugs designed to kill them—cause more than 2 million illnesses and 23,000 deaths each year in the United States alone. It is critical for scientists and researchers to be equipped with the right tools and the best information available to combat antibiotic resistance and improve antibiotic use. Better diagnostic tests are needed to help us characterize and identify resistant pathogens—an important component of diagnosing an infection early and accurately, and preventing spread of resistant infections. And new antibiotics are needed to more effectively treat infections with bacteria that have already developed resistance. One of the new resources available to researchers is the Antimicrobial Resistance Isolate Bank (AR Isolate Bank), which was launched in 2015 by the US Centers for Disease Control and Prevention (CDC). An AR isolate panel is removed from the freezer. Photo: CDC A collaboration between CDC and the US Food and Drug Administration (FDA), the AR Isolate Bank is a curated repository of nearly 400 unique AR pathogens pulled from CDC’s collection of more than 450,000 AR isolates and more than 18,000 characterized genomes. These curated isolate collections—called panels—provide researchers with well-characterized, resistant bacteria that can be used to develop effective and accurate next-generation diagnostics and accelerate research for new antibiotics. E.coli. Photo: CDC A timely example of the value of the AR Isolate Bank panels is its collection of E.coli isolates with the mcr-1 gene. Increasing reports of bacteria carrying mcr-1 genes have put public health experts across the globe on high alert. These genes can make bacteria containing them resistant to the crucial antibiotic colistin—a last resort drug being used to treat “nightmare bacteria” carbapenem-resistant Enterobacteriaceae. Within three weeks of identification of E.coli with the mcr-1 gene in the United States, the CDC assembled appropriate panels for the bank. Public health, industry, academic, and private labs can use these panels to calibrate their diagnostic tests so that they can ensure that bacteria carrying the mcr-1 gene are quickly and accurately identified and characterized. Findings from these calibrated tests will help public health partners ramp up targeted detection and response. The sample isolates can also help researchers build new tests to detect these types of resistance in the future—all to more quickly slow the spread of resistance.Since the launch of the AR Isolate Bank, more than 140 customers—including academic, commercial, federal, hospital and clinic, and public health laboratories—have requested panels. CDC is collaborating with FDA to support and expand use of this resource. At this time, the isolates are only available for shipment to recognized US laboratories with confirmed biosafety officers.The AR Isolate Bank is one small piece of CDC’s wide-ranging work to reduce the spread and impact of antibiotic resistant infections. CDC’s Antibiotic Resistance Solutions Initiative supports implementation of the surveillance, prevention, and stewardship activities outlined in the National Action Plan for Combating Antibiotic-Resistant Bacteria, which identifies critical actions to be taken by federal agencies to combat the emergence of resistant bacteria.

The US National Institutes of Health (NIH) announced the Antimicrobial Resistance Diagnostic Challenge last week, a competition which will award US$20 million for the development of rapid, point-of-care diagnostics to combat antimicrobial resistance. The competition will be funded by NIH's National Institute of Allergy and Infectious Diseases and the US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority, while the US Centers for Disease Control and Prevention and the US Food and Drug Administration will provide scientific and regulatory expertise. Eligible diagnostics are those that either test for drug-resistant bacteria or differentiate between viral and bacterial infections, critical tools to reduce ineffective and unnecessary antibiotic prescriptions. The recently launched Coalition for Epidemic Preparedness Innovations (CEPI) will fund early stage human clinical trials and stockpile vaccine candidates for the viruses most likely to cause the next major epidemic. CEPI will collaborate with product developers and the World Health Organization (WHO) to facilitate regulatory review of vaccine candidates and to ensure that large scale clinical trials can be rapidly rolled out in the case of an outbreak. Eligible vaccine candidates will target viruses identified by the WHO as the greatest threats, including Crimean Congo hemorrhagic fever, Ebola and Marburg, Lassa fever, Rift Valley fever, Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), and Nipah virus. The coalition was formed by the governments of India and Norway, philanthropic organizations the Wellcome Trust and the Bill & Melinda Gates Foundation, and the World Economic Forum and will be housed at the Norwegian Institute for Public Health in Oslo. The International Vaccine Institute (IVI) is partnering with Xiamen Innovax Biotech Co., Ltd. (Innovax) to expand access to the world’s first and only vaccine against Hepatitis E—a viral disease that causes 20 million infections and results in 70,000 deaths and 3,000 stillbirths each year. The vaccine, Hecolin®, was developed by Innovax and is only licensed for use in China. The Gates Foundation will support an assessment of the vaccine to determine its eligibility for WHO prequalification—a process that evaluates the safety, efficacy, and quality of a specific health tool produced by a specific manufacturer and that enables the product to be purchased by United Nations agencies. Hecolin® offered complete protection against hepatitis E in a phase 3 clinical trial with more than 100,000 participants. Pharmaceutical company Takeda has initiated a phase 3 clinical trial of its vaccine candidate against dengue fever, a mosquito-borne infection caused by four closely related viruses. Last year, pharmaceutical company Sanofi launched the world’s first dengue vaccine, however, new research suggests that the vaccine could actually increase the severity of infections in children who have never been exposed to dengue. This is due to antibody-dependent enhancement, in which protective antibodies against a virus (in this case, one strain of dengue virus) can actually help related viruses (the other three strains of dengue virus) attack human cells. Consequently, the antibodies produced by children receiving the vaccine could actually exacerbate the symptoms of future infections. In phase 1 and 2 trials, Takeda’s vaccine candidate appeared to be safe and resulted in the production of antibodies against all four strains of the virus. For its phase 3 trial, Takeda plans to enroll 20,000 children in dengue-endemic nations in Latin America and Asia. The trial will evaluate safety and efficacy against all four strains of dengue and in children with and without prior exposure to the virus.

The Toxoplasma gondii parasite is infamous for consuming brain tissue, causing brain cancer, and even altering the behavior of infected individuals. However, new research suggests that it could be modified and used to treat ovarian cancer. The team of scientists at Dartmouth University created a weakened version of T. gondii, removing the genes that enable the parasite to take over its host’s cells. Next, mice with aggressive ovarian cancer were inoculated with the weakened parasite. The study demonstrated that the presence of T. gondii, along with certain proteins excreted by the parasite, resulted in an enhanced immune response to ovarian cancer tumors. While none of the mice were completely cured—which could in part be attributable to the late stage of cancer at the time of treatment—those treated with the weakened parasite survived an additional 40 days on average. The World Health Organization (WHO) has issued new treatment guidelines for chlamydia, gonorrhea, and syphilis, as the three sexually transmitted infections (STIs) grow increasingly resistant to antibiotics. While resistant strains of chlamydia and syphilis are rare, multidrug-resistant gonorrhea has emerged in at least ten countries, and resistance to six classes of antibiotics has been reported. The WHO is calling for enhanced surveillance of drug-resistant strains of gonorrhea, and recommends that national treatment guidelines be determined based on local patterns of resistance. While syphilis is curable with a single dose of benzathine penicillin, the supply of the drug is low, and stock outs have been reported in a number of countries. While early stages of these three STIs are often asymptomatic, they can cause significant long-term damage, including pelvic inflammatory disease and infertility. Furthermore, they can be transmitted from mother-to-child during pregnancy and childbirth, and can increase the risk of ectopic pregnancy, miscarriage, stillbirth, and newborn death. As bacteria grow resistant to antibiotics, so too do fungi to antifungals. Each year, fungal infections result in 1 million deaths, and strains of both the aspergillus and candida fungi are growing resistant to the azole class of antifungals. While there are more than 20 classes of antibiotics, there are only four classes of antifungals, and thus, resistance to just one class of medicines is a major cause for concern. Scientists believe the leading cause of fungal resistance is the widespread use of fungicides on crops and in certain household paints and coatings. While dissecting mosquitoes in Guaico, Trinidad, researchers at the US Army Medical Research Institute of Infectious Diseases discovered a new and bewildering virus, configured unlike any other virus known to infect animals. Most viruses are comprised of a handful of genes packaged into one particle, however, the five genes of Guaico Culex exist as independent particles, and can only infect a mosquito if at least four of the five are present. Previously, viruses with this structure—known as multicomponent genomes—had only been found in plants and fungi. While humans are not susceptible to Guiaco Culex, a related virus has been found in monkeys, indicating that another multicomponent virus could infect humans.

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. In this edition, we cover new insights into the impact of the Zika virus on the brain. Researchers have released medical images of 46 fetuses and infants born to women who were infected with the Zika virus during pregnancy, revealing serious brain damage beyond microcephaly. The images, which include 23 MRI scans, 41 CT scans, and 93 ultrasounds, were taken at Instituto de Pesquisa in Campina Grande State Paraiba in northeastern Brazil and analyzed by neurologists at the Instituto in partnership with a team at the Beth Israel Deaconess Medical Center in Boston. The brain damage manifests in distinct ways: many of the scans showed skulls filled with cerebrospinal fluid, and in one case there was so little brain tissue that the skull collapsed in on itself, resulting in a flattened skull with extra skin. The images indicated damage to the brain stem, which regulates breathing and heart rate; the cerebellum, which is responsible for motor control; and the cortex, which is involved for learning, memory, emotion, and language. New research suggests that Hofbauer cells, found in the placenta and tasked with protecting the fetus from pathogens, may be the key to the Zika virus' ability to cross the maternal-fetal barrier. Hofbauer cells are macrophages, immune cells that combat pathogens by consuming them. However, dengue virus—a flavivirus related to Zika—is able to hijack macrophages, using them to replicate and disseminate throughout the body. While the researchers have confirmed that the Zika virus is able to survive within Hofbauer cells, they suspect that the immune cells may also be enabling the virus to travel to the fetal brain. The study also confirms that the virus can replicate within fibroblasts, a critical component of the placenta’s structure, a finding described as, “a bit of a surprise,” by one of the study’s authors. Scientists at Rockefeller University have also described their recent findings as "kind of a surprise," in this case, that certain adult brain cells are also susceptible to the virus. Fetal brains are primarily comprised of neural progenitor cells; while these stems cells are not as ubiquitous in adults, they play a critical role in learning and memory. Earlier this year, researchers determined that fetal neural progenitor cells are particularly vulnerable to Zika. Now, the team at Rockefeller has confirmed that adult neural progenitor cells are no exception. The study revealed an increase in cell death but a decrease in the production of new brain cells in infected adult mice. More research is needed to determine how this translates to humans, however, such damage could increase risk for cognitive challenges, depression, and Alzheimer’s disease.