Francesca Tomasi received her B.A. from the University of Chicago and currently does microbiology research.
The summer Olympics will start in Rio de Janeiro on August 5th. Unfortunately, the Olympics are not the only thing Brazil is hosting this year: the country’s northeast region is the epicenter of the ongoing Zika pandemic. The first rounds of clinical and laboratory studies have finally been published, and they concretely establish a link between Zika and pediatric microcephaly, as well as other forms of brain disruption in adults. At this point, it is important to remember that Zika causes mild (if any) symptoms in the vast majority of people. Most individuals who become infected with the virus will not experience neurological effects; similarly, most pregnant women who contract Zika will not deliver babies with microcephaly. That being said, however, the fact that Zika can cause (and has caused) such devastating conditions in thousands of people means it must be taken seriously and prevention must be prioritized. It is similar to Rubella in this respect – Rubella does not severely sicken most of the people it infects, but it does have the ability to adversely affect fetuses. This is why children every year are vaccinated against Rubella; large-scale vaccination creates herd immunity, which prevents an outbreak of the highly-contagious virus from occurring. Furthermore, future mothers do not run the risk of contracting the infection while they are pregnant. Measles and mumps are even milder viruses that cause unpleasant rashes and next to no neurological effects. Measles and mumps have not been linked to placental transmission but can be dangerous to newborns or immunocompromised children. As a result, vaccination of children against measles and mumps is listed as an essential immunization by the WHO. Case in point: Zika, too, causes a mild disease that can have severe outcomes in a subset of individuals. Thus it should be taken seriously the way measles, mumps, and Rubella are. The main difference is that Zika is spread by mosquitoes rather than from human-human contact, which makes it both easier and harder to control. We also do not have a vaccine yet, so additional preventive measures must be taken in the meantime.
As of May, 2016, Zika has spread to over 50 countries. Additionally, the World Health Organization recently announced that Zika is likely to spread to some parts of Europe by the end of spring. This announcement is based on a risk assessment that pooled together public health, climate, and mosquito data for each of the 53 member states in the European region. Regional dengue fever transmission was determined to be a good statistical precedent for Zika transmission as well, since the two viruses are related and transmitted by the same mosquito. Flocks of tourists and athletes traveling between Europe and Brazil for the Olympics, as well as to other parts of the world for summer vacation, are bound to give Zika plenty of opportunities to migrate over to Europe and any other currently naïve regions. For these reasons – and more specifically, that the country bearing the brunt of the outbreak is hosting the 2016 Olympics – many have argued in favor of canceling the Games or at least changing the Olympic venue. At least half a million people are expected to travel to Rio this summer. Back in January, the International Olympic Committee announced that Rio would be a “safe environment” for the Games, despite the spread of Zika in other parts of Brazil. However, in the past few months, data on just how many people are infected have been coming in. Not only is there Zika virus in Rio de Janeiro, but the virus’s incidence rate there is the fourth worst in Brazil at 157 per 100,000 people.
A counterargument to a feared spike in Zika cases in Rio is that Brazil is not in the Northern Hemisphere. So while it will be hosting the Summer Olympics this year, Rio will actually be doing so during its winter. This could mean a plummet in the local mosquito population due to cooler, dryer temperatures. Going back to the dengue surrogate for Zika, previous reports have shown that Brazilian dengue rates have in fact tended to peak in March and wane during the winter. Wane, however, is the operative word: dengue is not strictly seasonal the way the flu is; the flu spikes in the winter and virtually disappears in the summer. Dengue, however, can be very prevalent during the summer, and a little bit prevalent during the winter. In addition, despite these historical trends, Rio de Janeiro is actually currently facing an alarming rise in dengue cases, adding insult to the injury brought about by Zika. This news is coming despite Brazil’s biggest military mobilization in history: 220,000 members of the military and 315,000 public officials have been deployed to wage war against Aedes aegypti.
Half a million people converging into somewhat of a hot zone and then diverging back out to their respective home countries is an epidemiologist’s (and overall public health) nightmare. Of course, not all 500,000 foreigners are going to become infected with the virus. But if we take the current per capita estimate of Zika in Rio de Janeiro and apply it to the imminent tourist influx, we can reasonably expect at least 800 tourists to become infected (assuming the outbreak does not wane in the Brazilian winter, parallel to what seems to be happening with dengue this year). The numbers could be lower if people are vigilant about mosquito repellent, but they will not be zero.
Epidemiologically, it takes one infected individual to spark an outbreak: the Ebola epidemic in West Africa two years ago, for instance, started from a single “patient zero,” an infected toddler. Phylogenetic analysis (inferring evolutionary relationships between different samples to trace an organism or virus’s history) of the current Zika outbreak points to a single viral introduction in the country some time in 2013. Eight hundred infected travelers offer 800 opportunities for Zika to infiltrate a new pocket of the globe. Many infections in these pockets could be inconsequential – consider an Olympic spectator flying back to Norway, where one would be hard pressed to find a single Aedes mosquito – but others could be more significant in regions that harbor abundant Aedes aegypti and possibly Aedes albopictus.
Given the highly-interconnected nature of today’s world, Zika will inevitably spread wherever it can at one time or another. Such are the laws of networks (see: the world-wide spread of HIV, flu, and tuberculosis). Bringing together hundreds of thousands of people from all walks of life near the epicenter of an outbreak, only to send them back home after a few weeks, will only speed up the process, as one editorial describes. It is for this reason that some people are calling for the Olympics to be postponed, or at least for the venue to be changed. This has been done in the past with athletic events – this year, for instance, US baseball league games have been rescheduled and transferred out of Puerto Rico due to fears of Zika. In 1976, the Winter Olympics were moved from Denver, Colorado, to Innsbruck, Austria (for an entirely different environmental reason, but it happened). Furthermore, multiple ex-Olympic venues still have working facilities that could be used for the summer Olympics (London, Beijing, Athens, and Sydney). Both logistically and financially, this is not going to happen. But would it have happened if there have been serious conversations half a year ago?
Interestingly, the people talking about Zika in the context of the Olympics for the most part are not those directly involved with either the Games or the virus: the International Olympic Committee and the World Health Organization. One member of the Olympic committee went so far as to dismiss Zika as bogus: “If you are a young woman who is pregnant, and not many athletes will be, or planning to get pregnant, then there are precautions you should take. Beyond that, for me it’s a manufactured crisis,” said IOC member Dick Pound. Mr. Pound’s culpabilities are two-fold: for one, the majority of people flocking to Rio for the Games will not be athletes but rather friends, family, coaches, staff, and fans. Mr. Pound’s one-sided approach, only to consider the athletes in this crisis, goes against the Olympic mantra of universal respect and ethics. Furthermore, Mr. Pound is denying the concrete science of Zika’s potential (albeit rare) pathological consequences.
The World Health Organization was commendably quick to declare Zika a Public Health Emergency of International Concern, inciting the mobilization of medical and research institutions. The US Senate has approved a $1.1 billion measure to fight the virus (though people are calling for all of the originally requested $1.9 billion), and many other countries are rallying forces, including Brazil’s epic military mobilization. The WHO and CDC have issued travel advisories and recommendations for women planning on becoming pregnant, going so far as to advise that at-risk women postpone conceiving children until the virus is fully understood or the outbreak controlled. The National Institutes of Health and many other institutions are hard at work researching the virus and trying to find rapid diagnostics, treatments, and vaccines.
On Tuesday, the WHO issued a statement that the Olympics should not be postponed or moved. Margaret Chan, director-general of the WHO, said the decision came from the notion that "[y]ou don't want to bring a standstill to the world's movement of people. This is all about risk assessment and risk management." She then added that visitors to the Games should ensure that they wear adequate mosquito protection and that pregnant women should avoid travel to Brazil altogether. She did not address the specific risk assessments that went into this statement, specifically the epidemiology of bringing individuals (pregnant or not) somewhere they will soon leave and possibly take the virus with them. There are also other public health concerns about an Olympics in Rio, independent of Zika: for example, grimy water will undoubtedly affect rowers, sailors, and even some swimmers. In the case of Zika, most people have nothing to worry about. However, that should not justify knowingly increasing the speed with which the virus can spread. And what has the IOC done about contaminated water?
Interestingly, the IOC was ready to postpone or reschedule outdoor events in Beijing in 2008 due to concerns about smog. Air pollution is a public health threat that the IOC took seriously because of its direct impact on athletes. However, since Zika virus is probably not going to be a threat to most of the athletes competing (though the filthy waters will be for many), is it still the IOC’s responsibility to at least seriously address the virus and the Olympics’ location in tandem with other public health concerns? Yes. The Olympics are not exclusively about the athletes. The Olympics are supposed to be a symbol of, as China put it in their slogan 8 years ago, “One World, One Dream.” They are supposed to be “a chance…to come together as a human family for something.”
Of course, the Olympics will not be canceled, postponed, or relocated. They are barely 2 months away, and Brazil is surely gearing up for an incredible show. The country is also clearly working hard to control mosquitoes, between mass spray-downs and air conditioning unit installments to ward off the bugs. There are ways for travelers to prevent mosquito bites: that, often coupled with prophylaxis, is why travelers rarely contract malaria, dengue, and other tropical mosquito infections. Furthermore, the most at-risk individuals (pregnant women) have been advised to avoid travel to Brazil and other Zika-bearing nations. Nonetheless, the Olympics will surely facilitate the spread of Zika to new countries, and the IOC has been a little sloppy about responding to this. Its communication and reaction to the public health concerns surrounding this year’s Games could have been better. For now, however, we can get excited about some great athletics. Meanwhile, travelers should also be aware of the role they are capable of playing in the spread of Zika and how to minimize it.
Francesca Tomasi received her B.A. from the University of Chicago and currently does microbiology research.
In July, 1793, Philadelphia was the capital of the United States. It was an urban hub packed with colonists and free ex-slaves alike. The city bustled with the energy of a new nation as people came and left, conducting business and politics, building new lives for themselves.
In July, 1793, an outbreak of yellow fever ignited and tore through the city. In a matter of months, the infectious disease killed ten percent of Philadelphia’s population of 50,000 people, prompting 17,000 more residents to flee the city in a justifiably terrified frenzy. The outbreak raged through the summer and fall. Thomas Jefferson wrote many letters to friends and partners during the epidemic, describing both the outbreak and the panic that were plaguing the city. Here’s an excerpt from a letter to James Madison:
“A malignant fever has been generated in the filth of Water street which gives great alarm. About 70 people had died of it two days ago, & as many more were ill of it. It has now got into most parts of the city & is considerably infectious. At first 3 out of 4 died. Now about 1 out of 3. It comes on with a pain in the head, sick stomach, then a little chill, fever, black vomiting & stools, & death from the 2nd to the 8th day. Every body, who can, is flying from the city, and the panic of the country people is likely to add famine to disease. Tho becoming less mortal, it is still spreading, and the heat of the weather is very unpropitious. I have withdrawn my daughter from the city, but am obliged to go to it every day myself.”
Infection with the yellow fever virus starts with fever and muscle pain. Next come its first characteristic symptom, the namesake of the virus: victims develop jaundice as a result of liver and kidney failure. The most severe cases also developed a second characteristic, black vomit. In fact, the Spanish name for yellow fever is vomito negro, named after this symptom. This bloody vomit is a result of internal bleeding in the digestive tract. Delirium hits and as many as 89% of victims die.
The yellow fever outbreak came to a pretty abrupt end in November. There were many theories about its origin. One physician in Philadelphia named Benjamin Rush (you might recognize his name from the Declaration of Independence) thought the outbreak arose from contaminated, rotting coffee beans left on the city docks. He treated patients by bleeding them profusely and infusing them with mercury. Rush also believed that African Americans were immune to the disease, so he enlisted black volunteers as nurses. Of course, this theory turned out to be false, and African Americans soon became seriously ill and died at the same rates as white people.
Nothing was known about the yellow fever virus or how it spread until the end of the 19th century. Now, however, we know enough to have a vaccine that prevents the disease in much of the world. We know that the Philadelphia outbreak in 1793 was carried over from the Caribbean by refugees of an outbreak taking place there. We also know that a cold front in November ended the epidemic because the emerging winter frost killed off the city’s mosquito population.
Yellow fever is related to several viruses you may have heard of, including West Nile and Japanese encephalitis viruses. It is transmitted by infected Aedes and Haemagogus mosquitoes, which acquire the virus by feeding on infected humans and other primates. Today, yellow fever is rarely a cause of illness in the United States unlike in the 17th and 18th centuries. Instead, it is predominantly found in tropical and subtropical regions of South America and Africa.
There is a highly effective vaccine against yellow fever, which is why major outbreaks of the disease are so rare nowadays. The vaccine is recommended for anybody older than 9 months who lives in or is traveling to at-risk regions. In fact, many at-risk and neighboring nations require proof of vaccination for individuals traveling there. The yellow fever vaccine confers lifelong immunity in most people, another feature that contributes to its great effectiveness. There is currently no specific antiviral drug or immune therapy to treat someone who has been infected with the virus, which is why prevention is key.
Yellow fever had a happy ending in the United States and many other parts of the world. The vaccine has done an incredible job quelling this disease. However, a common theme in infectious diseases is the persistence of otherwise eradicated infections in poor regions lacking adequate public health infrastructure. This, coupled with a global shortage of the yellow fever vaccine, is triggering what some are calling a new global health emergency.
Zika virus has been getting a lot of attention lately because of its newfound neurological effects on developing fetuses and the fact that it is spreading like wildfire in parts of North and South America. However, an epidemic on one side of the world shouldn’t turn the world blind to a different epidemic raging somewhere else. Currently, the worst yellow fever epidemic in Angola is infiltrating the country (including the nation’s capital, Luanda). The outbreak began in December 2015, roughly the same time that Zika started gaining international attention. As of April 26, 2016, the disease has sickened over 2,020 people and killed at least 260. Infected travelers have also brought yellow fever to China, the Democratic Republic of Congo, Kenya, and Angola’s bordering nations Namibia and Zambia.
An article published by two members of faculty at Georgetown University calls for international attention to the outbreak. Notwithstanding the fact that over 7 million Angolans have been vaccinated against yellow fever, the ongoing global vaccine shortage could cause the epidemic in Angola to escalate as more people are infected and travel to other parts of the world where Aedes mosquitoes live (including the rest of Africa, Asia, and the Americas). The authors of the article call on the WHO to “convene an emergency committee to mobilize funds, coordinate an international response, and spearhead a surge in vaccine production.” They draw on “prior delays” by the WHO in assembling for these purposes such as during the 2014 Ebola epidemic, underscoring the hazard of not immediately and proactively addressing the unfolding yellow fever outbreak.
Earlier this month, the Democratic Republic of Congo announced a vaccination program against yellow fever aimed at immunizing 2 million individuals in Kinshasa and Kongo Central as a preventive strategy against the Angola outbreak: health officials in the DRC suspect local transmission of the virus and are working to quell a serious outbreak. This campaign, piled onto vaccination campaigns in the hard-hit nation of Angola, will really stretch the world’s yellow fever vaccine supplies thin, possibly even completely depleting them. For these reasons, people are calling on the WHO’s Emergency Use Assessment and Listing procedures, which were first used during the Ebola epidemic. These guidelines were established to expedite the availability of diagnostics, vaccines, and/or treatments in public health emergency situations. Such an intervention is highly called upon in the case of the ongoing yellow fever outbreak to prevent a possible pandemic. In this case, the WHO could authorize a reduced vaccine dose in order to reach more people while new vaccine stocks are produced. Of course, we don’t know the quality and duration of protection of a diluted vaccine. However, some protection is better than none, and such stewardship of existing vaccine stockpiles is a regulatory affair that requires official convening of an emergency committee. In the meantime, vaccine manufacturers should look into methods for vaccine development that do not require multi-stage egg incubation. Furthermore, mosquito control programs in the Americas currently being implemented to fight Zika should also make their way to Angola and neighboring regions.
Here’s what the WHO has to say about the outbreak in Angola, posted on April 13, 2016:
"The evolution of the situation in Angola is concerning and needs to be closely monitored. The reports of imported cases of YF in China, DRC and Kenya demonstrate that this outbreak constitutes a potential threat for the entire world. There is a risk for the further spread of the disease in view of the large international communities residing in Angola and the frequent travel activities with neighbouring and overseas countries. Furthermore, all countries where the mosquito vector (Aedes species) is present are at risk, notably those endemic for or previously affected by outbreaks of Dengue, Chikungunya or Zika virus and other arboviruses. Therefore, there is an urgent need to strengthen the quality of the response in Angola and to enhance preparedness activities in neighbouring countries and in countries that have diaspora communities in Angola. WHO continues to monitor the epidemiological situation and conduct risk assessment based on the latest available information."
Yellow fever now kills 80,000 Africans every year. As The Economist puts it bluntly yet accurately, “that is a scandal…because it can be prevented by a single inoculation.” This “scandal” will only explode if the current outbreak goes pandemic. Yellow fever vaccine production is controlled by the French drug company Sanofi Pasteur as well as institutes in Brazil, Senegal, and Russia. The world’s emergency yellow fever vaccine stockpile houses approximately 11 million doses. The ongoing outbreak, however, has the potential to go global if not controlled. If this turns out to be the case, 11 million doses will not even scratch the surface: should the virus reach naïve Asia (naïve meaning the virus has never before spread there), the number of people at risk would leap from tens of millions to over one hundred million.
Alessandra Tomasi received her B.A. from Cornell University and is now a first-year medical student.
We have previously discussed the potential treatment of glioblastomas using targeted immunotherapy against cytomegalovirus. A 2014 study also conducted at the Duke University Medical Center in Durham, North Carolina has pioneered investigations of the efficacy of another new approach to tumor treatment, also centered around a virus. This time, the treatment seeks to use a recombinant form of human poliovirus, the causative agent of polio. PVS-RIPO is the name of a genetically recombinant, live attenuated (non-pathogenic), oncolytic (tumor-killing) virus that only spreads in susceptible, non-neuronal cells, thereby rendering it highly specific to glioblastoma (GBM) tumors.
In order to be effective, oncolytic viruses in general must accomplish the following once they reach a tumor: (1) they must destroy a “cancer shield” that keeps the immune system from attacking the cancer cells, and (2) they must physically attack and kill the tumor itself. To do so, Duke’s modified poliovirus was first genetically modified virus to contain a portion of the rhinovirus genome. Rhinoviruses cause the common cold, which is obviously a much less severe infection than polio. This modification prevents the poliovirus vector from replicating, reverting, or actually causing polio. The virus is then infused directly into a patient's brain via placement of a catheter, in order to maximize the amount of virus that will reach a tumor for efficacious targeting and killing.
The modified poliovirus has tumor-specific binding (i.e. it will reach and attack a tumor) because cancer cells express receptors that directly attract the poliovirus. Viral infections always require some sort of receptor to which the virus can bind and initiate infection. CD155 is a transmembrane protein found on the surface of certain non-neuronal cells in humans. CD115 is more commonly known simply as the poliovirus receptor given its involvement in viral adherence and infection, but, conveniently, it also plays a role in mediating tumor cell invasion and migration. Once the modified PVS-RIPO reaches its target cells, it attaches to CD155 to establish “infection,” then enters the cells (for any biologists out there, it exploits a ribosomal entry site for internalization). In this way, the modified virus harnesses a patient’s own immune system to fight cancer by eliciting an inflammatory response. This response includes the recruitment of various immune cells to initiate a cascade that will eventually – hopefully – lead to tumor cell death.
Our bodies have the means to destroy certain kinds of cancer cells via the immune system’s many powerful components that can work synergistically to defeat an unwanted visitor. It’s quite possible that the future of cancer treatment is a matter of triggering a targeted, amplified immune response at the site of a budding tumor.