Virus World

Takeda has laid out considerable time, effort and money on its dengue vaccine program despite Sanofi's trouble with its earlier entrant. Now, the Japanese drugmaker is touting phase 3 data showing the vaccine was 80% effective at preventing dengue.

In a study called Tides, investigators tested the Takeda vaccine, TAK-003, against placebo in more than 20,000 participants aged four to 16 in dengue-endemic countries in Latin America and Asia. Twice as many participants received the vaccine as those who received placebo. In those who received both doses, the vaccine was 80.2% effective, the team reported Wednesday. Investigators tracked 61 cases of dengue in the vaccine group versus 149 in the placebo group, according to results published in The New England Journal of Medicine. 

Importantly, efficacy varied among dengue serotypes. The vaccine was 73.7% effective against dengue serotype 1, 97.7% effective against serotype 2 and 62.6% effective against serotype 3. The investigators didn't track enough serotype 4 cases to reach an efficacy determination. The shot was 95.4% effective in preventing dengue that required hospitalization; there were five hospitalizations in the vaccine group versus 53 in the placebo group. The company has said it expects phase 3 studies to form the basis for regulatory submissions. Derek Wallace, Takeda’s dengue vaccine program chief, told FiercePharma the company is “encouraged by the data” as the results demonstrate the vaccine “has a potential to have a very big impact” on the dengue burden worldwide.

Takeda is particularly pleased about the vaccine’s performance in participants who hadn't had a prior dengue infection, Wallace said. In that group, the vaccine was 74.9% effective in preventing dengue. Pharma watchers may remember that Sanofi's dengue vaccine, the world's first, tripped up because of safety problems in those who hadn't had prior infections. The French drugmaker rolled out the shot in 2016, but in late 2017, the company said a new analysis had found it could cause more serious disease in those who’d been infected before. The disclosure triggered outrage in the Philippines, where officials had started a vaccination campaign. All told, the scandal knocked Sanofi’s vaccine off its launch trajectory and the company faced numerous questions about the vaccine's safety and its rollout in the Philippines. Dengvaxia originally had blockbuster expectations, but in 2018, its sales weren’t significant enough for Sanofi to disclose. Still, Takeda isn't backing down from the dengue vaccine challenge. The company just this week opened a €130 million plant in Germany to meet global demand for the shot once it launches. The drugmaker plans to employ up to 200 workers at the plant. 

Clinical Study published in New England Journal of Medicine (November 6, 2019):

https://doi.org/10.1056/NEJMoa1903869

Better knowledge of the face of the current dengue virus (DENV) epidemiology in Africa can help to implement efficient strategies to curb the burden of dengue fever. We conducted this systematic review and meta-analysis to determine the prevalence of DENV infection in Africa. We searched PubMed, EMBASE, African Journals Online, and Africa Index Medicus from January 1st, 2000 to June 10th, 2019 without any language restriction.

We used a random-effects model to pool studies. A total of 76 studies (80,977 participants; 24 countries) were included. No study had high risk of bias. Twenty-two (29%) had moderate and 54 (71%) had low risk of bias. In apparently healthy individuals, the pooled prevalence of DENV was 15.6% (95% confidence interval 9.9–22.2), 3.5% (0.8–7.8), and 0.0% (0.0–0.5) respectively for immunoglobulins (Ig) G, IgM, and for ribonucleic acid (RNA) in apparently healthy populations. In populations presenting with fever, the prevalence was 24.8% (13.8–37.8), 10.8% (3.8–20.6k) and 8.4% (3.7–14.4) for IgG, IgM, and for RNA respectively. There was heterogeneity in the distribution between different regions of Africa.

The prevalence of DENV infection is high in the African continent. Dengue fever therefore deserves more attention from healthcare workers, researchers, and health policy makers.

Study Published on Scientific Reports (Open Access):

https://doi.org/10.1038/s41598-019-50135-x

Mosquitoes are more likely to acquire the dengue virus when they feed on blood with low levels of iron, researchers report. Supplementing people's diets with iron in places where both iron deficiency anemia and dengue fever are a problem could potentially limit transmission of the disease, but there are risks.

Dengue fever is a disease spread by mosquitoes in the tropics, primarily Central America and northern South America, the Caribbean, sub-Saharan Africa and southeast Asia. It has also been transmitted in the southeastern US. Dengue causes a fever, rash, and terrible aches, and can also lead to shock and death. It causes about 60 million cases a year, with 18% requiring hospitalization and about 13,600 deaths, and costs about $9 billion annually worldwide. 

Dengue is most commonly acquired in urban environments, and the expansion of cities in the tropics has been accompanied by an expansion in dengue infections. A vaccine exists, but it can actually make the disease worse if given to someone who has never been previously infected. Public health officials are actively looking for ways to reduce the prevalence of the disease. 

UConn Health immunologist Penghua Wang wanted to see if blood quality had an impact on the spread of dengue virus. Blood levels of various substances can vary tremendously from person to person, even among healthy people. Wang and colleagues at Tsinghua University and State Key Laboratory of Infectious Disease Prevention and Control in Beijing, King Mongkut's Institute of Technology Ladkrabang in Bangkok, and the 920 Hospital Joint Logistics Support Force in Kunming ran a series of experiments to explore the idea.  They collected fresh blood from healthy human volunteers, then added dengue virus to each sample. Then they fed the blood to mosquitoes, and checked how many mosquitoes were infected from each batch. They found it varied quite a lot. And the variation correlated very closely with the level of iron in the blood.

"The more iron in the blood, the fewer mosquitoes were infected," says Wang. The team found it held true in a mouse model, too: mosquitoes feeding on mice infected with dengue were much more likely to acquire the virus if the mice were anemic. The reason has to do with the mosquitoes' own immune systems. Cells in a mosquito's gut take up iron in the blood and use it to produce reactive oxygen. The reactive oxygen kills the dengue virus. 

"In areas where dengue is endemic, iron deficiency is more common. It doesn't necessarily explain it, the high prevalence of dengue...but it could be possible that iron supplementation could reduce dengue transmission to mosquitoes in those areas," Wang says. But there's a big caveat. Malaria tends to be common in the same areas as dengue. And plasmodium, the microorganism that causes malaria, thrives in an iron rich environment and might actually worsen if everyone is supplementing with iron. Public health authorities need to weigh the costs and benefits before embarking on any population-wide supplementation program....

Published on September 16, 2019 in Nature Microbiology:

https://doi.org/10.1038/s41564-019-0555-x

An initial infection with dengue virus did not prime monkeys for an especially virulent infection of Zika virus, according to a study at the University of Wisconsin-Madison. Nor did a bout with Zika make a follow-on dengue infection more dangerous. As outbreaks on Pacific islands and in the Americas in recent years made Zika virus a pressing public health concern, the Zika virus's close similarity to dengue presented the possibility that one infection may exacerbate the other. Dengue virus infections are infamous for being bad the first time around. But following infection with one of the four variants (called serotypes) of dengue with an infection by a different serotype can amplify the already dangerous symptoms—high temperature, fatigue and pain—and make dengue fever even more life-threatening.

"When that second dengue virus occurs, antibodies kind of recognize it, but not in a way that allows them to take the virus out of the system and neutralize it like normal," says Dawn Dudley, a scientist in the University of Wisconsin-Madison's Department of Pathology and Laboratory Medicine and one of the authors of the new Zika study. "Instead, they have kind of a secondary effect, where by binding to the virus loosely they actually enhance the ability of the virus to get into other cells in the body and replicate more."  The study of 21 Wisconsin National Primate Research Center macaque monkeys, in which animals infected with one virus were challenged with another within nine to 12 months, supports the human epidemiological results. "Whether it was a primary infection with one of the dengue serotypes followed by a Zika infection, or Zika first with a later dengue infection, we didn't see anything unusual in those secondary infections," says UW-Madison pathology research specialist Meghan Breitbach, also an author of the study.

But it comes with a caveat important to Zika: none of the study's monkeys were pregnant. Zika's most visible and troubling results are neurological problems in babies whose mothers were infected during pregnancy, though those complications vary widely.  Dengue fever is enhanced by an earlier dengue infection only during certain conditions dependent on the serotypes of dengue involved, whether the immune memory produced by the initial infection was relatively strong or weak, and how much the antibodies created may have faded over months or years. The complicating factors have led to caution in development of Zika and  dengue vaccines for fear of sparking more severe infections later. "Our study suggests that that is unlikely," Newman says. "But as we learn more about people whose infections come two or three years apart, we may see we need to combine a Zika vaccine with a good vaccine against all four serotypes of dengue virus to prevent enhancement of either virus"

Findings published on August 1, 2019 in PLOS Pathogen:

https://doi.org/10.1371/journal.ppat.1007766

Of Honduras' 32 public hospitals, 26 are overflowing with patients due to what health authorities are calling the worst dengue fever epidemic in the past half century. The disease has struck 28,000 people this year, of which 54, mostly children, have died.

Officials have called a national emergency to fight the dengue-causing aedes aegypti mosquito and a fumigation program has been launched in homes and public buildings. The only effective measure to halt the epidemic "is to destroy the mosquito's breeding grounds and this is something that every one of us has to do in our homes, where we work and also in every public area," said Hernandez. It's a critical situation with the three-month long rainy season about to begin, meaning that breeding grounds will soon proliferate and the mosquito's numbers could soar.

Dengue infection (DI) is the most important arboviral infection in the world. The majority of immunocompetent patients will have asymptomatic or mild infections, but the degree of dengue severity in kidney transplant recipients (KTx) is unknown. In recent decades, the growing number of organ transplant recipients in developing countries, living in or traveling to an endemic area of dengue, is at risk of developing this infection. Additionally, in kidney transplant recipients (KTx), DI may be associated with other viral infections, such as cytomegalovirus (CMV), increasing the risk for the recipients after renal transplantation (Tx). Because CMV remains one of the most important viruses affecting KTx, it is not clear whether the CMV coinfection may modify the outcome of DI as it usually does in other viral coinfections

In this study, we report the clinical profile and outcomes of 39 dengue cases in KTx. From a total of 1,186 KTx outpatients in follow-up we reviewed clinical and laboratory records of 60 (5%) patients admitted with suspected DI initially screened by NS-1, IgM, and when possible, multiplex nested PCR. The prevalence of DI in KTx was 3% (39/1,118), with symptoms leading to hospital admission being fever, myalgia, malaise, and headache.

Laboratory tests showed leucopenia, thrombocytopenia, and liver enzyme elevation. DI was confirmed by positivity of NS-1 (33%), IgM (69%), and/or RT-PCR (59%). Twenty-three patients (59%) had dengue with warning signs, and 15% had severe dengue, 2 of them with a fatal course. Acute graft dysfunction occurred in 59% (mean nadir serum creatinine: 2.9 ± 2.6mg/dL), 4 of them requiring dialysis. CMV coinfection diagnosed in 19% of the cases and patients was associated with worse clinical presentation.

Our results suggest that KTx with DI presented initial physical and laboratorial profile similar to the general population. However, DI in KTx seems to have a higher risk for graft dysfunction, severe dengue, and death. Because CMV coinfection aggravates the DI clinical presentation and recovery, it must be evaluated in all cases.

Published in PLOS One (October 30, 2019):

https://doi.org/10.1371/journal.pone.0219117

Dengue virus (DENV) infects about 400 million people annually around the world, with a high prevalence in tropical and sub-tropical regions.The virus causes diseases ranging from mild dengue fever to severe dengue haemorrhagic fever and dengue shock syndrome.

DENV2 exists as smooth spherical surface particles while growing at the mosquito’s physiological temperature (29 degrees Celsius). It then changes to bumpy surfaced particles at human physiological temperature (37 degrees Celsius). This ability to morph helps the virus to evade the immune system of the human host. Hence, understanding the mechanism behind this is important for therapeutics and vaccine development. “Together with Professor Pei-Yong Shi from UTMB, we found that in laboratory developed DENV2 strains, mutations in the virus’ E protein causes its transformation into bumpy particles. These structural changes can cause vaccines and therapeutics to be ineffective against the virus,” said Ms Xin-Ni Lim, the study’s lead author who is from Duke-NUS’ Emerging Infectious Diseases (EID) Programme.

The team also tested four DENV2 strains obtained from patients. They observed that in contrast to the laboratory adapted viruses, the majority of these clinical strains maintained smooth surface structure at 37 degrees Celsius. However, at 40 degrees Celsius, the temperature of a fever, all virus strains took on a bumpy surface. “Our study gives a new direction to vaccine development and treatment for dengue disease. For prevention of disease through vaccines that are administered to the patient before dengue infection, we should use those that are effective against the smooth surface virus. When it comes to patients displaying fever symptoms, treatment strategies effective against the bumpy surface particles should be implemented,” said Dr Sheemei Lok, Professor, Duke-NUS’ EID and corresponding author of this study.

“This study is a first step towards gaining more insight into how DENV2 reacts and adapts to the host’s immunological defenses. We were also able to use computational modelling approaches to predict why particles from different DENV2 strains are more or less adept at morphing from the smooth to bumpy structures. By better understanding the interactions between the virus and the host, we will be able to develop better therapies and vaccines to treat or prevent infections, and contribute to public health outcomes,” said Dr Peter Bond, Principal Investigator from A*STAR’s BII.  The study’s findings also show that the lab adapted DENV2 may not be a good model for research, as its structure is different from the clinical strains isolated from patients. The team is planning to study the other DENV serotypes to find out if there are any other possible structural changes.

Study published on September 19, 2019 in PLOS Pathogens (Open Access):

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1007996

Researchers led by Duke-NUS Medical School have discovered that tryptase, an enzyme in human cells that acts like scissors to cut up nearby proteins, is responsible for blood vessel leakage in severe dengue hemorrhagic fever. The finding suggests a possible new treatment strategy using the tryptase inhibitor, nafamostat mesylate, for severe dengue disease—a potentially fatal condition for which no targeted treatment is currently available.

The dengue virus infects about 390 million people globally each year, causing substantial morbidity and mortality. While most patients experience dengue fever or a mild form of the disease, a small percentage develops dengue hemorrhagic fever (DHF), the more severe occurrence of dengue wherein blood 'leaks' from ruptured blood vessels. This can lead to dengue shock syndrome (DSS) – the final stage of DHF—where the circulatory system fails, sending the body into bleeding and shock, which is fatal without prompt treatment. 

How dengue patients go on to develop these severe conditions had not been clearly understood and, as a result, no targeted treatments have been developed to prevent hemorrhaging or reverse shock in infected patients. "We discovered that, in severe cases, a particular enzyme called tryptase cuts the proteins that act as seals between blood vessel cells, resulting in blood vessel leakage and shock during dengue infection," said Assistant Professor Ashley St. John, from Duke-NUS' Emerging Infectious Diseases Programme, corresponding author of the study.

Based on this finding, the team wanted to know if a drug specific to inhibiting tryptase could be used to treat the hemorrhaging. Nafamostat mesylate, a clinically-approved tryptase inhibitor with a good safety profile, was tested using preclinical models. They found that administration of this drug, which is already used for the treatment of certain bleeding complications in some countries, prevented vascular leakage in the dengue model. Even delayed treatment with the drug was significantly effective in reducing dengue vascular leakage in a preclinical model of severe disease. The team also observed tryptase levels were very high in the blood of severe dengue patients who experienced DHF/DSS, but low in patients who easily recovered, affirming the link between high levels of the enzyme and severe dengue disease.

The findings were first published on July 2, 2019 in the Journal of Clinical Investigation:

https://doi.org/10.1172/JCI128426

The female mosquito needs your blood to grow her eggs. Please don’t feel singled out. She bites everyone. There is no truth to the myths that mosquitoes prefer women over men or blondes and redheads over those with darker hair. She does, however, play favorites. Type O blood seems to be the vintage of choice. Stinky feet emit a bacterium that woos famished females, as do perfumes. As a parting gift, she leaves behind an itchy bump (an allergic reaction to her saliva) and potentially something far worse: infection with one of several deadly diseases, including malaria, Zika, West Nile, dengue and yellow fever.

The FDA has granted investigational new drug status to PrimeVax’s combo therapy, which uses dengue virus and dendritic cells to fight cancer. The investigational new drug (IND) application is for patients with melanoma (skin cancer) who have failed prior immune checkpoint inhibitors. Hospital sites are being prepared to start dosing patients with the therapies. 

“Today, I am proud to report that we have successfully built [the] dengue virus into our clinical design, and have gained alignment with FDA on this novel therapeutic approach,” Tony Chen, PrimeVax’s CEO, said in a press release. PrimeVax is developing a multi-mechanism treatment strategy that takes advantage of the body’s  immune system to fight malignant cells. It combines immune cells called stimulatory dendritic cells with the dengue virus to trigger a broader and stronger immune response against resistant cancer cells. 

The company established an exclusive agreement with the U.S. Army to use a specific dengue virus strain (dengue virus-1 #45AZ5) to treat cancer in January 2019. This dengue strain has a zero mortality rate and is well-tolerated. By using the Army’s dengue virus, researchers aim to induce a systemic fever in a controlled manner. This will trigger a common immune response and create a pro-inflammatory status in patients, activating the therapeutic dendritic cells to specifically target the malignant cells. To evaluate the safety and effectiveness of this strategy, the company is launching three Phase 1 clinical trials in patients with advanced melanoma. The main goal is to identify the best treatment protocol and potential safety issues. Researchers will also evaluate the anti-cancer activity of the different approaches by determining response and survival rates.