Congenital Zika Syndrome

FlavivirusData from several clinical studies in Brazil establish a strong link between infection of pregnant women with Zika virus and a variety of birth defects collectively called congenital Zika syndrome.

In the latest study conducted in Rio de Janeiro, the authors enrolled 88 pregnant women who had a rash in the previous 5 days. Of the 88 subjects, 72 tested positive for Zika virus by PCR. Fetal ultrasound was performed in 42 of the Zika virus positive women, and in all the Zika virus negative women.

The results are convincing: fetal abnormalities were detected in 12 of the 42 Zika virus positive women (29%) and in none of the Zika virus negative women.

The abnormalities include fetal death (2), microcephaly (5), ventricular calcification or other central nervous system lesions (7), and abnormal amniotic fluid volume or cerebral or umbilical artery flow (7). These observations show that Zika virus infection may lead to birth defects other than microcephaly.

The infections of these pregnant women with Zika virus took place throughout pregnancy, from week 8 to week 35. This window of susceptibility is in contrast to rubella virus which is more likely to cause birth defects when infection occurs in the first trimester.

Not all Zika virus infections seem to cause birth defects – 29% in this study. If this number holds outside of Rio de Janeiro, then birth defects should also be observed in other countries with high rates of infection. Only 20% of Zika virus infections are symptomatic, and it will be important to determine if these also lead to congenital Zika syndrome.

The increase in microcephaly associated with Zika virus infection was first noted in the northeast of Brazil. This study was done with women who live in Rio de Janeiro, in the southeast of Brazil, showing that the association is not geographically limited.

It has been suggested that fetal defects might be partly due to the presence of antibodies to dengue virus that cross-react with Zika virus and cause immune-mediated enhancement of disease. Thirty-one percent of the Zika virus positive women in this study were also positive for antibodies to dengue virus, but the paper does not report how these correlate with fetal defects.

These findings, together with results of previous studies showing recovery of the entire Zika virus genome from amniotic fluid or from fetal brain, demonstrate that this fast spreading and newly emerging virus infection is clearly a threat to the developing fetus.

We should not be surprised that a virus that had until recently only infected several thousand individuals, and which we believed caused a mild, self-limiting rash, suddenly is found to be extremely dangerous to the developing fetus. The potential for fetal damage was likely always present, but unobserved until the virus was introduced into a large population of susceptible individuals and hundreds of thousands of individuals were infected. The lesson to be learned, often easily forgotten, is that we should always expect more from viruses than we initially observe. Such was certainly the case for HIV-1; immunodeficiency was only the tip of the clinical syndrome caused by infection.

Given the pace at which Zika virus is racing through susceptible humans, it is likely to generate enough population immunity in the next five years to curtail this outbreak. However as susceptible individuals are born and accumulate, regular outbreaks will likely occur. Similarly, outbreaks of rubella virus in the US occurred every 5-6 years in the pre-vaccine era.

Not only do rubella and Zika viruses cause similar fetal and placental abnormalities, in the mother they both lead to rash, joint pain, skin itching, and lymphadenopathy without high fever.

Hopefully the similarities between rubella virus and Zika virus will stop there: it took nearly 30 years to develop a rubella virus vaccine after the discovery that infection caused birth defects.

 

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.

TWiV 341: Ebolavirus experiences

On episode #341 of the science show This Week in Virology, Vincent returns to the University of Glasgow MRC-Center for Virus Research and speaks with Emma, Gillian, and Adam about their ebolavirus experiences: caring for an infected patient, working in an Ebola treatment center in Sierra Leone, and making epidemiological predictions about the outbreak in west Africa.

You can find TWiV #341 at www.microbe.tv/twiv.

TWiV 340: No shift, measles

On episode #340 of the science show This Week in Virology, the TWiV teams reviews a MERS-coronavirus serosurvey and an outbreak in South Korea, and constraints on measles virus antigenic variation.

You can find TWiV #340 at www.microbe.tv/twiv.

The Wild Types

The Wild Types is an interview show about scientists hosted by Ushma Neill and Richard White. Ushma interviewed me for episode #2. The show name doesn’t refer to the fact that all scientists are wild (some are; I am not) but the genetic term referring to the strain or organism that is compared with mutants. As in, ‘the wild type virus was compared with the mutant virus that transmits among ferrets by the airborne route’.

 

The quarantine period for Ebola virus

Cost BalancingWHO and CDC recommend that individuals who are potentially infected with Ebola virus should be quarantined for 21 days. Where does this number come from? Charles Haas at Drexel University asked the same question, and provides an answer.

The quarantine period for an infectious disease is based on the incubation period, the time before symptoms of an infection appear. For Ebola virus, the incubation period is 2-21 days after infection. During this time it is believed that individuals infected with the virus are not contagious, but they could produce small amounts of virus. Whether or not a patient is contagious during the incubation period depends on the virus.

It is clearly important to determine the correct quarantine period for Ebola virus to prevent chains of infection. The longer the quarantine period imposed, the less risk of infecting others. However the cost of enforcing quarantine must be balanced with the cost of releasing exposed individuals (illustrated). According to Haas, the optimal quarantine time should be at the intersection of the two curves.

To determine how the Ebola virus quarantine period was set at 21 days, Haas examined the incubation periods calculated for previous outbreaks. In a study of the 1976 Zaire outbreak, the mean time between exposure and disease for 109 cases of person-to-person spread was calculated at 6.3 days with a range of 1 to 21 days. Mean incubation times for the 1995 Congo outbreak (315 cases) and the 2000 Uganda outbreak (425 cases) were 5.3 and 3.35 days, respectively. Two other analyses of the 1995 Congo outbreak gave mean incubation times of 10.11 and 12.7 days. WHO has estimated a mean incubation period for the first 9 months of the current west African outbreak as 11.4 days, with an upper limit (95% confidence) of 21 days.

Haas concludes that the 21 day quarantine value is derived from a ‘reasonable interpretation’ of outbreak data, but it might not be long enough. He estimates that there is a risk of between 0.2% and 12% of developing Ebola virus infection after 21 days.

The current outbreak should allow collection of data for revising and updating the 21 day quarantine period for Ebola virus infection.

 

WHO assessment of experimental Ebola virus vaccines

The World Health Organization held a conference to assess the status of testing and eventual licensing of two candidate Ebola virus vaccines. The agenda and list of participants and the final report are available. I was interested in the following list of key expected milestones:

October 2014:
Mechanisms for evaluating and sharing data in real time must be prepared and agreed upon and the remainder of the phase 1 trials must be started

October–November 2014:
Agreed common protocols (including for phase 2 studies) across different sites must be developed

October–November 2014:
Preparation of sites in affected countries for phase 2 b should start as soon as possible

November–December 2014:
Initial safety data from phase 1 trials will be available

January 2015:
GMP (Good Manufacturing Practices) grade vaccine doses will be available for phase 2 as soon as possible

January–February 2015:
Phase 2 studies to be approved and initiated in affected and non-affected countries (as appropriate)

As soon as possible after data on efficacy become available:
Planning for large-scale vaccination, including systems for vaccine financing, allocation, and use.

I wonder how a phase 2 study will be conducted, the goal of which is to determine if it is effective and further evaluate its safety. Will this be done in west Africa, where protection against Ebola virus infection can be assessed? If so, will there be controls who receive placebo?

If indeed an Ebola virus vaccine is our best hope in limiting the current outbreak, it won’t be distributed for a while, according to the optimistic expectations of WHO – assuming all proceeds on time, and that the results are favorable.

Enterovirus D68 infections in North America

EV-D68

Enterovirus D68 by Jason Roberts

An outbreak of respiratory disease caused by enterovirus D68 began in August of this year with clusters of cases in Missouri and Illinois. Since then 691 infections have been confirmed in 46 states in the US.

The number of confirmed infections is likely to increase in the coming weeks, as CDC has developed a more rapid diagnostic test. Previously it was necessary to amplify the viral genome by polymerase chain reaction, followed by nucleotide sequencing to determine the identity of the agent. The new test utilizes real time, reverse transcription PCR which is specific for the EV-D68 strains that have been circulating this summer.

Since its discovery in California in 1962, EV-D68 has been rarely reported in the United States (there were 26 isolations from 1970-2005). Beginning in 2009 it was more frequently linked to respiratory disease outbreaks in North America, Europe, Asia, and Africa. It seems likely that the virus was always circulating, but we never specifically looked for it.

The current EV-D68 outbreak is the largest ever reported in North America. Enterovirus infections are not rare – there are millions every year in the US – but why EV-D68 has been so frequently isolated this year is unknown. One possibility is that the CDC, after the initial outbreak in August 2014, began looking specifically for the virus.

Sequence analysis of the EV-D68 viral genomes indicate that 3 different strains are involved in the US outbreak. These viruses are related to EV-D68 strains that have previously circulated in the US, Europe, and Asia. The sequences are available at GenBank as follows: US-IL-14/18952, US-KY-14/18951, US-MO-14/18950, US-MO-14/18949, US-MO-14/18948, US-MO-14/18947, and US-MO-14/18946.

Most of the illness caused by EV-D68 in the US has been respiratory disease, mainly in children. Five of the 691 confirmed EV-D68 cases were fatal, but whether the virus was responsible is not known.

There have also been some cases of polio-like illness in children in several states associated with EV-D68. In Colorado the virus was isolated from four of 10 children with partial paralysis and limb weakness. Previously there had been one report of an association of EV-D68 with central nervous system disease. In this case viral nucleic acids were detected in cerebrospinal fluid. EV-D68 probably does not replicate in the human intestinal tract because the virus is inactivated by low pH. If the virus does enter the central nervous system, it may do so after first replicating in the respiratory tract, and then entering the bloodstream.

There are no vaccines or antivirals to prevent or treat EV-D68 infection. Most infections will resolve without intervention save for assistance with breathing. As the fall ends in North America, so will infections with this seasonal virus.

Could the Ebola virus epidemic have been prevented?

Ebola is comingThe cover of this week’s issue of Businessweek declares that ‘Ebola is coming’ in letters colored like blood, with the subtitle ‘The US had a chance to stop the virus in its tracks. It missed’. Although the article presents a good analysis of the hurdles in developing antibody therapy for Ebola virus infection, the cover is overstated. Why does Businessweek think that Ebola virus is coming to the US? (there is no mention of this topic in the article). Are we sure that antibody therapy would have stopped the outbreak? (no, as stated in the article).

How the U.S. Screwed Up in the Fight Against Ebola is an analysis of why ZMapp, the cocktail of monoclonal antibodies that block infection with Ebola virus, has not yet been approved for use in humans. ZMapp was given to two American workers who had become infected with the virus while working in Africa. The two workers recovered, but the role of ZMapp in their recovery is unknown – as the authors of the article note. Although ZMapp can prevent lethal infection of nonhuman primates with Ebola virus, it is not known if it would work in humans. Answering that question requires a clinical trial, and the article explores why this phase was not done years ago. Only after the large Ebola virus outbreak in west Africa did the US provide funds to conduct a phase I trial of the drug.

The article discusses how development of ZMapp languished for years, because the US government did not consider the Ebolaviruses to be a pressing problem. In hindsight they were wrong, and now anyone can seem smart by saying we should have pushed development of Ebola virus vaccines and therapeutics.

The real question is whether we will learn from this experience, and be better prepared for the next viral outbreak. Just because infections are rare or geographically localized should not lessen their importance, as these features can change. Knowing the animal source of a viral infection may also lead to developing ways to prevent infections. For example, because people acquire Hendra virus from horses, immunization of these animals should prevent human infections.

What other antiviral vaccines and drugs should we be developing? This question is difficult to answer because we discover new viruses regularly and making therapeutics for all of them is not possible. Testing an antiviral drug or vaccine against rare viruses is difficult because identifying populations that are at risk for infection may be a hit or miss proposition.

Influenza viruses are at the top of the list for vaccine and drug development, because nearly everyone gets infected. Other viruses we should be ready for include SARS and MERS coronaviruses, dengue virus, chikungunya virus, Lassa virus, Nipah and Hendra viruses. I’m sure you can think of other viruses that belong on this list.

Developing antiviral vaccines and drugs is expensive. For some of the viruses on my list (dengue, chikungunya) there are currently large enough markets that permit involvement of for-profit pharmaceutical companies. Development of therapeutics against viruses that cause rare infections must be supported largely by governments.

The US does not spend enough money on basic life sciences research. We do spend a great deal of money on the military. President Obama recently declared Ebola virus to be a top national security priority. Why not view all infectious diseases in this way, to ensure that they receive the funding for research that they deserve?

While the Businessweek cover is misleading, intended to stimulate sales, the article does make us think about the problems we confront when dealing with rare but lethal diseases. No one should conclude that Ebola virus outbreak in Africa could have been prevented, because antiviral therapies have not yet been tested in humans. But we won’t know if we never do the research.

TWiV 304: Given X, solve for EBOV

On episode #304 of the science show This Week in Virology, the TWiV team consults an epidemiologist to forecast the future scope of the Ebola virus epidemic in West Africa.

You can find TWiV #304 at www.microbe.tv/twiv.