Breakthroughs Blog: Vaccines

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.

The House Energy & Commerce Committee recently passed an amendment—attached to an unrelated bill—that would add requirements for eligibility to the Tropical Disease Priority Review Voucher (PRV) program at the US Food and Drug Administration (FDA). The PRV program, established by Congress in 2007, is intended to incentivize research and development (R&D) for drugs for which there is a critical need but a limited market opportunity. Under the program, the regulatory sponsor of an approved drug for a tropical or rare pediatric disease is awarded a voucher which expedites FDA review of a future product by four months. These vouchers enable companies to enter the market sooner, and several have been sold between companies for up to US$350 million. Of the three vouchers that have been awarded for tropical disease drugs, two were awarded to companies that weren’t actually involved in the drug’s development—they had merely acquired rights to the drug—and in one case, the drug was already approved by other regulatory authorities and available in 80 countries. The amendment, introduced by Congressman G.K. Butterfield (D-NC), would require the regulatory sponsor to demonstrate the need for the product (i.e., the global burden of the disease and demand for the product) and elucidate their plan to ensure access to the product. Vienna-based researchers have developed a vaccine against Toxic Shock Syndrome (TSS), a rare, life-threatening condition resulting from an extreme immune system response to a Staphylococcus infection. TSS is associated with the use of super absorbent tampons, and an estimated half of cases occur in menstruating women. In a phase 1 clinical trial, the vaccine candidate—which contains a detoxified strain of Staphylococcus—proved to be safe and successfully prompted an immune response. The vaccine will next be tested in a larger, phase 2 trial. The team anticipates the vaccine will last for five years and will be used to protect individuals with a compromised immune system who are at greater risk for TSS. Nature took an in-depth look at drug repositioning, in which a medicine developed to treat one disease or condition is used to treat another. Drug repositioning is not a new concept; leading drugs against HIV and AIDS and erectile dysfunction were once intended to treat cancer and angina, respectively. However, the practice is becoming more common. Since 2011, the number of journal articles published on repurposed drugs has increased sixfold to an average of 30 per month and each year three to four new companies focused solely on the practice are established. Generic medicines are a common target, however, there are also many drugs that have passed phase 1 or clinical trials, proving to be safe for use in humans, but that did not have the intended effect. This approach makes drug development cheaper and faster, as phase 1 trials can often be skipped. Repositioning a drug costs $300 million and takes 6.5 years, compared to $2 to 3 billion and 13 to 15 years when starting from scratch. However, phase 1 trials may still be needed if the drug needs to be delivered in a different way or if a different dose is needed. Additionally, many pharmaceutical companies have massive, untapped compound libraries and new technology and software have made it easier to discover ways in which distinct conditions manifest similarly on a molecular level, which allows them to better identify promising compounds to screen for a given condition or disease.

Schistosomiasis, the second most common parasitic disease, infects more than 240 million people each year, and can result in liver failure, bladder cancer, and even death. Schistosomiasis is treated using the antiparasitic drug Praziquantel, however, resistance to the drug has been reported in Kenya and Uganda. Despite its efficacy, the mechanism of action of Praziquantel remains a mystery; scientists don’t understand how it combats schistosomiasis. By comparing the genomes of parasites that are sensitive and resistant to the drug, researchers at the Texas Biomedical Research Institute and the University of Texas have identified genes that are associated with resistance, and have received a US$3.5 million grant from the US National Institutes of Health to further examine the individual genes and mutations that confer resistance. The team will collect parasite eggs from patients in Kenya and Uganda before and after treatment with Praziquantel; the eggs from patients who are cured and those that remain infected will be classified as sensitive and resistant to the drug, respectively. They will then sequence the parasites’ genomes, honing in on the genes and mutations linked to resistance, with the goal of better understanding how resistance develops. This information is critical to developing drugs that are effective against Praziquantel-resistance parasites and diagnostics that can detect resistance. Researchers at the All India Institute of Medical Sciences (AIIMS) have completed successful animal trials of an oral vaccine against hepatitis B using a nanotechnology platform that could be adapted for other viruses. Oral vaccines are challenging to develop, as the key components are often degraded in the stomach before they can be absorbed through the intestines. However, they offer significant advantages: they don’t require needles and consequently there’s no risk of blood contamination, many don’t need to be kept cold, and they often spread more thoroughly throughout the immune system. The existing vaccine against hepatitis B is injectable and requires three to four doses, whereas the vaccine under development at AIIMS could be potent enough to require just a single dose. The team used nanoparticles to house the antigen—the part of the vaccine that triggers an immune response—and covered the nanoparticles in a protective surface that can survive the stomach. The vaccine will next be tested in human clinical trials, which the team hopes to complete by 2021. The World Health Organization (WHO) is proposing new guidelines for yellow fever vaccination in emergencies, as alarming outbreaks in Angola, Uganda, and Peru intensify due to a limited global supply. Clinical trials suggest that the vaccine is effective at much smaller doses, and the WHO is expected to recommend that member states use just one fifth of the standard dose. However, the studies were conducted exclusively in adults, raising concerns that the fractional dose might not be enough to protect children. It’s also unclear if the smaller dose would provide lifelong immunity, and the WHO’s proposal will likely recommend a booster to be administered at a later time. Once complete, the proposal will be submitted to the WHO’s Strategic Advisory Group of Experts on Immunization for review, and if approved, will be implemented if the outbreak reaches emergency levels.

Last Wednesday, researchers from the Washington University School of Medicine, the University of São Paulo, and the Chinese Academy of Sciences offered new insights into the impact of the Zika virus on fetal brain development in mice, publishing their findings in Cell, Nature, and Cell Stem Cell, respectively. The first two studies sought to successfully infect pregnant mice with Zika—a feat in itself as mice don’t often fall ill after infection with the virus. Consequently, the team at Washington University used a genetically modified mouse with a weakened immune system as well as a mouse whose immune system was weakened by an antibody, while researchers at the University of São Paulo used a particularly high dose. The team at Washington University detected placental insufficiency in the infected mice—which limits blood flow to the fetus—and the team at University of São Paulo reported intrauterine growth restriction, a condition restricting the growth of the fetus. When the virus reached the fetal brains, both teams witnessed a thinning of brain tissue and cell death. The concentration of the virus in the brain was limited, which inhibited further research on how Zika behaves once in the brain. The team at the Chinese Academy of Sciences, however, injected the virus directly into the brains of fetal mice, and they determined that the virus targets neural progenitor cells and causes the fetal brain to shrink. Silk has been used in developing heat-stable vaccines and drugs, and now, researchers at Tufts University have demonstrated that silk can be used to maintain blood samples in low-resource settings. Blood-based diagnostics are only effective if certain proteins, which indicate either the presence of a pathogen or the immune system’s response to it, are preserved, however, heat and humidity can directly damage the proteins or cause enzymes in the blood to attack the proteins. Labs prefer that blood samples are refrigerated, although they can also be dried on special filter paper that can withstand heat but which often doesn’t hold enough blood for analysis. The team at Tufts created a silk-based powder and solution, combined it with blood samples, and allowed it to dry. The samples were then stored at high temperatures (72 to 113ºF) and remained viable for 84 days. GHTC member the International Vaccine Institute (IVI) announced last week that a single dose of the oral cholera vaccine Shanchol, currently administered in two-dose regimens, provides protection against the disease. The two-dose regimen provides 65 percent protection against cholera for at least five years, while the single dose demonstrated 40 percent protection against the disease for at least six months. While the two-dose regimen is preferred, the single dose could be appropriate for epidemics or in settings where the two-dose vaccine schedule is impractical. The study enrolled 204,700 individuals residing in the urban slums of Mirpur in Dhaka, Bangladesh, where cholera is endemic. In addition to reducing cases by 40 percent, the vaccine resulted in a 63 percent decrease in cases of severely dehydrating cholera.