Zika virus and mosquito eradication

Aedes aegyptiThe Aedes aegypti eradication campaign coordinated by the Pan American Health Organization led by 1962 to elimination of this mosquito from 18 countries, including Brazil. Ae. aegypti transmits not only Zika virus, but dengue virus, chikungunya virus, and yellow fever virus. Could control measures be implemented today to achieve similar control of this mosquito? Two articles in PLoS Neglected Tropical Diseases revisit the successful PAHO mosquito control campaign and suggest that its approaches should be revived.

The elimination of Ae. aegypti in 18 countries, which was accompanied by a marked reduction in dengue hemorrhagic fever, was achieved by removing mosquito breeding sites or spraying them with DDT. Determining whether households harbored such breeding sites was essential for the effectiveness of the campaign.

The United States did not participate in the PAHO campaign, even though Ae. aegypti was (and still is) present in that country, and was a vector for outbreaks of dengue fever from the 1920s through the 1940s. Peter Hotez (link to paper) cites a “lack of funds and political will” and “logistical difficulties due to lack of access to private homes or cultural norms of privacy in the US”. As a consequence, by 1970 the US became one of the last reservoirs of Ae. aegypti in the Americas.

Eventually the PAHO campaign fell apart and Ae. aegypti returned, followed by outbreaks of dengue fever in the 1980s in Latin America and the Caribbean, and Chikungunya virus and Zika virus in 2013.

Hotez argues that while control of Ae. aegypti is labor intensive and involves house-to-house spraying, PAHO demonstrated its feasibility. He further suggests that by not participating in the PAHO campaign, the US failed to establish a generation of mosquito control expertise, which is now needed as Zika virus and other mosquito-borne viruses threaten to spread. He calls for an “unprecedented campaign against the Ae. aegypti mosquito”. However, he does not specify exactly what kind of control should be implemented, only saying that “these activities might not closely resemble the Latin American programs of the 1960s”.

Paul Reiter (link to paper) believes that the success of the PAHO campaign “can be attributed to a single aspect of the behavior of the mosquitoes: female Ae. aegypti do not lay all their eggs in one basket”, but rather place them at multiple locations. During the PAHO campaign, infested containers were identified and sprayed with DDT, increasing the likelihood that a female would lay eggs at a site that had been treated. This approach is called perifocal.

The current use of fogging machines to spray residential areas with insecticides has a low impact on mosquito populations, according to Reiter, because they only work for a few minutes when the droplets are airborne. He believes that we should return to perifocal treatments to eliminate mosquitoes, but not using DDT. Rather he suggests the use of other, novel insecticides, such as crystals of deltamethrin embedded in a rain and sun-proof polymer that ensures release for three months.

Reiter acknowledges that long-term use of insecticides leads to resistance, in which case we should turn to the new anti-mosquito approaches that are being developed, including the release of mosquitoes containing Wolbachia bacteria or a lethal gene. But he indicates that these approaches “are some way from mass application”, and meanwhile, perifocal approaches could reduce mosquito populations (although the newer insecticides would first need to be tested).

The best way to prevent viral infection is with a vaccine, but one for Zika virus is likely years away. Meanwhile, mosquito control can make a difference, as it could for the next emerging virus well before a vaccine can be developed.

TWiV 392: Zika virus!

Four virologists discuss our current understanding of Zika virus biology, pathogenesis, transmission, and prevention, in this special live episode recorded at the American Society for Microbiology in Washington, DC.

You can find TWiV #392 at microbe.tv/twiv, or listen/watch below.

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TWiV 387: Quaxxed

TWiVOn episode #387 of the science show This Week in Virology, Nina Martin joins the TWiV team to talk about the movie Vaxxed, her bout with dengue fever, and the latest research on Zika virus.

You can find TWiV #387 at microbe.tv/twiv, or listen below.

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From trivalent to bivalent oral poliovirus vaccine

Antibodies bound to poliovirusFor the first time since April of 1955, recipients of poliovirus vaccine will no longer receive all three serotypes. This past Sunday the World Health Organization orchestrated a synchronized switch from trivalent to bivalent oral poliovirus vaccine (OPV) in 150 countries.

The reason for the switch is clear: type 2 poliovirus was declared eradicated last year, and the only remaining cases are cause by vaccine-derived type 2 polioviruses. After oral administration of poliovirus vaccine, the virus replicates in the intestine, conferring immunity to subsequent infection. In all recipients of the vaccine the viruses lose the mutations that make them safe for humans. Consequently a small number of recipients, and their contacts, contract poliomyelitis from the vaccine.

To prevent further cases of poliomyelitis caused by circulating vaccine-derived polioviruses, WHO planned a synchronized, global switch from trivalent OPV to bivalent OPV on 17 April 2016. By July of 2016 all remaining stocks of the Sabin type 2 poliovirus strains, which are used to produce OPV, will also be destroyed.

My concern with this strategy is that type 2 vaccine-derived polioviruses continue to circulate. Whether they will continue to do so long enough to cause an outbreak of paralytic disease in the cohort of new infants that do not receive type 2 vaccine is a mattern of conjecture. In case there is an outbreak, monovalent type 2 oral poliovirus vaccine is being stockpiled by WHO. Of course, re-introduction of this vaccine will be accompanied by more circulating vaccine-derived poliovirus in the environment, and vaccine-associated disease, the very event WHO is trying to end with the trivalent to bivalent switch.

Type 3 poliovirus has not been isolated since 2012. Only type 1 poliovirus still causes outbreaks in two countries: Pakistan and Afghanistan. The inability to vaccinate in those countries, due to conflict, is delaying eradication. The recent killing of seven police officers who were protecting polio vaccinators by the Pakistani Taliban is an example of this difficulty.

Developing a great vaccine is not the only requirement for preventing infectious disease: you also have to be able to deploy it.

Image: Antibodies bound to poliovirus by Jason Roberts.

TWiV 384: Agent 003, a view to a fish kill

TWiVMass die-offs of tilapia by a novel orthomyxo-like virus, Ian Lipkin’s editorial on the movie Vaxxed, and new vaccines to prevent dengue virus infections, including a human challenge model, are topics of episode #384 of the science show This Week in Virology. With guests Ian Lipkin and Nischay Mishra from the Center for Infection and Immunity.

You can find TWiV #384 at microbe.tv/twiv, or listen below.

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TWiV 375: Zika and you will find

TWiVOn episode #375 of the science show This Week in Virology, the TWiVziks present everything you want to know about Zika virus, including association of infection with microcephaly and Guillain-Barré syndrome, transmission, epidemiology, and much more.

You can find TWiV #375 at microbe.tv/twiv.

Zika virus

FlavivirusThe rapid spread of Zika virus through the Americas, together with the association of infection with microcephaly and Guillain-Barré syndrome, have propelled this previously ignored virus into the limelight. What is this virus and where did it come from?

History
Zika virus was first identified in 1947 in a sentinel monkey that was being used to monitor for the presence of yellow fever virus in the Zika Forest of Uganda. At this time cell lines were not available for studying viruses, so serum from the febrile monkey was inoculated intracerebrally into mice. All the mice became sick, and the virus isolated from their brains was called Zika virus. The same virus was subsequently isolated from Aedes africanus mosquitoes in the Zika forest.

Serological studies done in the 1950s showed that humans carried antibodies against Zika virus, and the virus was isolated from humans in Nigeria in 1968. Subsequent serological studies revealed evidence of infection in other African countries, including Uganda, Tanzania, Egypt, Central African Republic, Sierra Leone, and Gabon, as well as Asia (India, Malaysia, Philippines, Thailand, Vietnam, Indonesia).

Zika virus moved outside of Africa and Asia in 2007 and 2013 with outbreaks in Yap Island and French Polynesia, respectively. The first cases in the Americas were detected in Brazil in May 2015. The virus circulating in Brazil is an Asian genotype, possibly imported during the World Cup of 2014. As of this writing Zika virus has spread to 23 countries in the Americas.

The virus
Zika virus is a member of the flavivirus family, which also includes yellow fever virus, dengue virus, Japanese encephalitis virus, and West Nile virus. The genome is a ~10.8 kilobase, positive strand RNA enclosed in a capsid and surrounded by a membrane (illustrated; image copyright ASM Press, 2015). The envelope (E) glycoprotein, embedded in the membrane, allows attachment of the virus particle to the host cell receptor to initiate infection. As for other flaviviruses, antibodies against the E glycoprotein are likely important for protection against infection.

Transmission
Zika virus is transmitted among humans by mosquito bites. The virus has been found in various mosquitoes of the Aedes genus, including Aedes africanus, Aedes apicoargenteus, Aedes leuteocephalus, Aedes aegypti, Aedes vitattus, and Aedes furcifer. Aedes albopictus was identified as the primary vector for Zika virus transmission in the Gabon outbreak of 2007. Whether there are non-human reservoirs for Zika virus has not been established.

Signs and Symptoms
Most individuals infected with Zika virus experience mild or no symptoms. About 25% of infected people develop symptoms 2-10 days after infection, including rash, fever, joint pain, red eyes, and headache. Recovery is usually complete and fatalities are rare.

Two conditions associated with Zika virus infection have made the outbreak potentially more serious. The first is development of Guillain-Barré syndrome, which is progressive muscle weakness due to damage of the peripheral nervous system. The association of Guillain-Barré was first noted in French Polynesia during a 2013 outbreak.

Congenital microcephaly has been associated with Zika virus infection in Brazil. While there are other causes of microcephaly, there has been a surge in the number of cases during the Zika virus outbreak in that country. Whether or not Zika virus infection is responsible for this birth defect is not known. One report has questioned the surge in microcephaly, suggesting that it is largely attributed to an ‘awareness’ effect.  Current epidemiological data are insufficient to prove a link of microcephaly with Zika virus infection. Needed are studies in which pregnant women are monitored to see if Zika virus infection leads to microcephaly.

Given the serious nature of Guillain-Barré and microcephaly, it is prudent for pregnant women to either avoid travel to areas that are endemic for Zika virus infection, or to take measures to reduce exposure to mosquitoes.

Control
There are currently no antiviral drugs or vaccines that can be used to treat or prevent infection with Zika virus. We do have a safe and effective vaccine against another flavivirus, yellow fever virus. Substituting the gene encoding the yellow fever E glycoprotein with that from Zika virus might be a good approach to quickly making a Zika vaccine. However testing of such a vaccine candidate might require several years.

Mosquito control is the only option for restricting Zika virus infection. Measures such as wearing clothes that cover much of the body, sleeping under a bed net, and making sure that breeding sites for mosquitoes (standing water in pots and used tires) are eliminated are examples. Reducing mosquito populations with insecticides may also help to reduce the risk of infection.

Closing thoughts
It is not surprising that Zika virus has spread extensively throughout the Americas. This area not only harbors mosquito species that can transmit the virus, but there is little population immunity to infection. Infections are likely to continue in these areas, hence it is important to determine whether or not Zika virus infection has serious consequences.

Recently Zika virus was identified in multiple states, including Texas, New York, and New Jersey, in international travelers returning to the US . Such isolations are likely to continue as long as infections occur elsewhere. Whether or not the virus becomes established in the US is a matter of conjecture. West Nile virus, which is spread by culecine mosquitoes, entered the US in 1999 and rapidly spread across the country. In contrast, Dengue virus, which is spread by Aedes mosquitoes, has not become endemic in the US.

We recently discussed Zika virus on episode #368 of the science show This Week in Virology. You can be sure that we will revisit this topic very soon.

Added 1/28/16 9:30 PM: The letter below to TWiV provides more detail on the situation in Brazil.

Esper writes:

Hi TWIVomics

I hope this email finds you all well and free of pathogenic viruses.

My name is Esper Kallas, an ID specialist and Professor at the Division of Clinical Immunology and Allergy, University of São Paulo, Brazil.

I have been addicted to TWIV since a friend from U. Wisconsin participated in the GBV-C episode (David O’Connor, episode #260). Since then, never missed one episode. After long silent listening, I decided to write for the first time, motivated by the ongoing events in my country, potentially related to the Zika virus.

In the last episode, Emma wrote about events taking place in the small town of Itapetim, State of Pernambuco, Northeastern Brazil, which I will describe a bit later in this email. Before, let me bring some background information on the current situation.

Most believed Zika was a largely benign virus, causing a self-limited disease, clearly described in episode #368. Its circulation was documented after an outbreak became noticed in the State of Bahia (NE Brazil) by a group led by Guilherme Ribeiro, a talented young Infectious Diseases Scientist from Fiocruz (PMID: 26584464, Emerg Infect Dis. 2015 Dec;21(12):2274-6, free access)

However, things started to get awkward around October 2015, when a single hospital in Recife (NE Brazil) and some other practicing Obstetricians and Pediatricians from the region started reporting a mounting number of microcephaly cases in newborns, later confirmed by the national registry of newborns. The numbers are astonishing. The graph below depicts the number of cases per year prior to the surge in 2015. Only this year, 2,975 cases were reported by December 26, the vast majority in the second semester of the year. Cases are concentrated in the Northeast (map), with 2,608 cases, including 40 stillbirths or short living newborns.

Microcephaly, Brazil

In response to the situation, the Brazilian Ministry of Health has declared a national public health emergency (http://portalsaude.saude.gov.br/index.php/cidadao/principal/agenciasaude/20629-ministerio-da-saude-investiga-aumento-de-casos-de-microcefalia-em-pernambuco).

The Brazilian Ministry of Health has been presenting updates every week (see link: http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/leia-mais-o-ministerio/197-secretaria-svs/20799-microcefalia). It is important to observe some imperfections in these numbers: 1. There may be an over reporting after the news made to the big media, suggesting an association between microcephaly and Zika virus. 2. The criterion to consider a microcephaly case has been changed after the current epidemic from 33cm to 32cm; this is because 33cm of head circumference is sitting in the 10th percentile of newborns at 40 weeks of pregnancy and the adjustment would bring the limit to the 3rd percentile, increasing the specificity to detect a true microcephaly case (this may result in an over reporting in the beginning of the epidemic).

The association between Zika virus infection and microcephaly was suspected since the beginning, when Brazilian health authorities ruled out other potential causes, together with the fact that the microcephaly epidemic followed Zika virus spread. Further evidences were the two positive RT-PCR for Zika RNA in two amniotic fluids obtained from two pregnancies of microcephalic fetuses and a stillborn microcephaly case with positive tissues for Zika RNA. In fact, French Polynesia went back to their records and also noticed an increase of microcephaly case reporting, following their epidemic by the same virus strain in 2013 and 2014.

Now, Zika virus transmission has been detected in several countries in the Americas (http://www.paho.org/hq/index.php?option=com_topics&view=article&id=427&Itemid=41484&lang=en).

Although strong epidemiological data suggest the association between Zika virus and the microcephaly epidemic, a causal link between the virus and the disease is still lacking and is limited to few case reports. Many questions still remain. Does the virus damage embryonic neural tissue? What is the percentage of fetuses getting infected when the mother acquires Zika virus during pregnancy? Does the stage of pregnancy interfere with virus ability to be transmitted to the fetus and the development of neurologic effects? Are there other neurological defects related to Zika virus infection? Is there another cofactor involved, such as malnutrition or other concurrent infection? All these questions are exceedingly important to provide counseling to pregnant women and those who are planning to become pregnant, especially in Northeastern Brazil. In fact, Brazilian authorities have been recommending avoiding pregnancy until this situation is further clarified.

The microcephaly epidemic impact is unimaginable. It is a tragedy. These children are compromised for life and the impact on their families is beyond any prediction.

Back to the story sent by Emma. A small town in the North of Pernambuco State, named Itapetim, has almost 14 thousand inhabitants and has reported 11 cases of microcephaly in the past 3 months. This very same town has been suffering from a prolonged drought, since September 2013 when the last reservoir went dry. Perhaps the storage of clean water or the limited resources has led to the best environment for arbovirus spread and the development of microcephaly.

But the Zika virus’s impact may be reaching further. An increase in Guillain-Barré syndrome cases has also been noticed in the Northeast of Brazil, possibly related to the epidemic.

Several groups have been trying to establish animal models to study the interaction of Zika virus with neural tissue. The forthcoming developments are critical to better understand the virus immunopathology and confirm (or refute) the association between the virus infection and neurologic damage in fetuses and in the infected host developing Guillain-Barré syndrome. Many things still shrouded in mystery.

Keep on the good work. I will keep on listening!

Esper

TWiV 373: The distinguished virology career of Julius S. Youngner

On episode #373 of the science show This Week in Virology, Vincent speaks with Julius about his long career in virology, including his crucial work as part of the team at the University of Pittsburgh that developed the Salk inactivated poliovirus vaccine.

You can find TWiV #373 at microbe.tv/twiv. Or you can watch the video below.



The switch from trivalent to bivalent oral poliovirus vaccine: Will it lead to polio?

bivalent OPVIn four months, 155 countries will together switch from using trivalent to bivalent oral poliovirus vaccine. Will this change lead to more cases of poliomyelitis?

There are three serotypes of poliovirus, each of which can cause paralytic poliomyelitis. The Sabin oral poliovirus vaccine (OPV), which has been used globally by WHO in the eradication effort, is a trivalent vaccine that contains all three serotypes.

In September 2015 WHO declared that wild poliovirus type 2 has been eradicated from the planet – no cases caused by this serotype had been detected since November 1999. However, in 2015, there were 9 cases of poliomyelitis caused by the type 2 vaccine. For these reasons WHO decided to remove the type 2 Sabin strain from OPV, and switch from trivalent to bivalent vaccine in April 2016.

After OPV is ingested, the viruses replicate in the intestinal tract, providing immunity to subsequent infection. During replication in the intestine, the vaccine viruses lose the mutations that prevent them from causing paralysis. Everyone who receives OPV sheds these revertant viruses in the feces. In rare cases (about one in 1.5 million) the revertant viruses cause poliomyelitis in the vaccine recipient (these cases are called VAPP for vaccine-associated paralytic poliomyelitis). Vaccine-derived polioviruses can also circulate in the human population, and in under-vaccinated populations, they can cause poliomyelitis.

There were 26 reported cases of poliomyelitis caused by the type 1 or type 2 vaccine viruses in 2015. Nine cases of type 2 vaccine-associated polio were detected in four countries: Pakistan, Guinea, Lao People’s Democratic Republic, and Myanmar. Removing the type 2 strain from OPV will eliminate vaccine-associated poliomyelitis in recipients caused by this serotype. When the US switched from OPV to the inactivated poliovaccine (IPV) in 2000, VAPP was eliminated.

The problem with the trivalent to bivalent switch is that vaccine-derived type 2 poliovirus is likely still circulating somewhere on Earth. The last two reported cases of type 2 vaccine-associated polio in 2015 were reported in Myanmar in October. The viruses isolated from these cases were genetically related to strains that had been circulating in the same village in April of the that year. In other words, type 2 vaccine-derived strains have been circulating for an extended period of time in Myanmar; they have been known to persist for years elsewhere. If these viruses continue to circulate past the time that immunization against type 2 virus stops, they could pose a threat to the growing numbers of infants and children who have not been immunized against this serotype.

Eventually as type 3, and then type 1 polioviruses are eradicated, it will also be necessary to stop immunizing with the respective Sabin vaccine strains. The switch from trivalent to bivalent vaccine in April 2016 is essentially an experiment to determine if it is possible to stop immunizing with OPV without placing newborns at risk from circulating vaccine-derived strains.

Over 18 years ago Alan Dove and I argued that the presence of circulating vaccine-derived polioviruses made stopping immunization with OPV a bad idea. We suggested instead a switch from OPV to IPV until circulating vaccine-derived viruses disappeared. At the time, WHO disagreeed, but now they recommend that all countries deliver at least one dose of IPV as part of their immunization program. Instead of simply removing the Sabin type 2 strain from the immunization programs of 155 countries, it should be replaced with the inactivated type 2 vaccine. This change would maintain immunity to this virus in children born after April 2016. Such a synchronized replacement is currently not in the WHO’s polio eradication plans. I hope that their strategy is the right one.

TWiV 370: Ten out of 15

On episode #370 of the science show This Week in Virology, the TWiVomics review ten captivating virology stories from 2015.

You can find TWiV #370 at www.microbe.tv/twiv.