First Zika virus vaccine enters phase 1 trials in US.

A healthy volunteer receives the NIAID Zika virus investigational DNA vaccine as part of an early-stage trial to test the vaccine’s safety and immunogenicity. This is the first administration of this vaccine in a human.
Credit: NIAID

The National Institute of Allergy and Infectious Diseases (NIAID) made a press announcement on August 3,2016 about its recent launch of phase I clinical trials for its newly developed DNA Zika vaccine.

Zika is rife in Puerto Rico, American Samoa, the US Virgin Islands, and Florida and United States department of defense(DoD) recently confirmed about 30 cases of Zika virus infection among troops. As per Florida Department of Health recent update there are 15 total number of non-travel related infections and 55 pregnant patients have been infected due to either local transmission, sex with an infected partner or travel.[1] A total of more than 6,400 Zika cases have been reported in the US and its territories.[2]  

The NIAID Zika virus vaccine is investigational and was developed in the beginning of this year. The vaccine contains bio-engineered, non-infective Zika virus plasmid that contains genetic code for protein of the Zika virus. When injected into our body by intramuscular route, the DNA quickly assemble into a virus like particle, that has lost its infecting capabilities. It incites an immune response in the host by making antibodies and T cells.

The DNA vaccine, is delivered on the site on skin via a short electrical pulse that propels the DNA, which seeks  human cells through a process called electroporation.

It is also known from the animal experiment that despite being genetically different, all strains of the Zika virus have identical surface antigen, thereby vaccine developed against one will be effective against others too. [3]

According to John Mascola, MD, director of NIAID’s Vaccine Research Center (VRC), “DNA or gene-based vaccines include antibodies, but they also can activate the cell-mediated immune response, which ultimately could yield strong and durable protection against disease.”

DNA vaccines are new in the vaccine armament and no other DNA vaccine has been approved by US.[4] But since they do not need to grow live virus, DNA vaccines have short development time.[5]

The vaccine will be tested in 80 healthy volunteer in Maryland and Atlanta. The volunteers will receive the first shot at the same time and then they are divided into 4 groups of 20 each receiving the subsequent shots at varying intervals to study which dosing schedule works best. All the participants will be closely monitored for 44 weeks of initial vaccine administration.[6]They will be tested to measure the immune response to the vaccine at 18 and 24 months after the initial dose.

Researchers have already tested the vaccines in animal studies and found them to be effective and safe. When monkeys were exposed to Zika virus 4 weeks after the second dose, they showed no clinical signs of infection nor the virus was found in the blood.[7]

Meanwhile, a similar vaccine developed by The Infectious Disease Research Centre (IDRC) and the Centre de recherche du CHU (Centre hospitalier de l’Université) at Laval University in Canada has also begin its phase 1 clinical trials.

The vaccine is temporarily named GLS-5700, and is manufactured by Inovio, based in Plymouth Meeting, Pennsylvania, and GeneOne Life Science, of Seoul, South Korea.

At this point of time around 18 countries around the world are competing each other to develop Zika virus vaccines including French pharmaceutical giant Sanofi SA and GlaxoSmithKline.

According to CDC Zika virus infection is a public health emergency because of its causation of congenital birth defects. Currently 61 countries and territories are infected with Zika virus and 12 countries have reported birth defects due to Zika.

If the phase 1 trial is successful, the vaccine will enter phase 2 trial in early part of 2017. But, even at this pace it will be another 2 years before it is commercially available.

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[1] http://www.floridahealth.gov/newsroom/2016/08/080316-zika-update.html

[2] https://www.niaid.nih.gov/news/newsreleases/2016/Pages/Zika-Investigational-Vaccine.aspx

[3] https://www.niaid.nih.gov/news/newsreleases/2016/Pages/Zika-serotype.aspx#

[4] https://www.statnews.com/2016/08/03/nih-zika-vaccine-trial/?trendmd-shared=0

[5] http://fortune.com/2016/01/28/zika-virus-vaccine/

[6] http://www.contagionlive.com/news/niaid-zika-vaccine-enters-clinical-trial

[7] https://www.niaid.nih.gov/news/newsreleases/2016/Pages/3-Zika-Vaccine-Approaches.aspx#

First female to male sexual transmission of Zika virus documented in New York.

Yet another very important update on sexual transmission of Zika virus from CDC was published online in CDC's Morbidity and Mortality Weekly Report[1]

Till now it was known that sexual transmission of ZIKA virus only takes place from male to female partner. But, The New York City Department of Health and Mental Hygiene (DOHMH) today identified the first case of a female transmitting the Zika virus to a man through sex in New York city.

This surprising new announcement have prompted the CDC to update its guidelines on the sexual mode of transmission of the virus.

A 20-year-old non-pregnant woman had condomless vaginal intercourse with male partner on the day she returned from a country where Zika virus infection is ongoing. She was completely symptomless on the day of return, but was down with Zika-like symptoms, including fever, rash, fatigue and muscle pain, along with numbness and tingling in her fingers and toes. On the next day she visited her primary health care provider, who confirmed the illness as Zika virus after getting the results of her urine and blood test. ((rRT-PCR). 

A week after the sexual contact, the male partner also had similar symptoms and was also diagnosed with Zika infection. On detailed history he ruled out other mode of Zika transmission. He has not travelled outside the country since 1 year, only had one sexual encounter since a week and did not have any mosquito bite.

Both the partners tested negative for Zika virus IgM antibodies by the CDC Zika MAC-ELISA assay performed at the New York State Department of Health Wadsworth Center.

CDC report concluded that “The timing and sequence of events support female-to-male Zika virus transmission through condomless vaginal intercourse.” The woman was most likely viremic when she had sex with her partner, and the virus was transmitted through uretral mucosa or penile abrasion or cut from woman’s vaginal or menstrual blood.   

A case report published on May 2016 in Lancet has already documented the presence of Zika virus in female genital tract.[2] Non-Human studies in primates have shown the presence of the virus in genital tract up to 7 days after subcutaneous inoculation.[3]

This case is very important from public health perspective as until now, it was assumed that the Virus is transmitted from a male partner to a receptive partner, now ongoing surveillance will be needed to combat the additional risk of reverse transmission. CDC is also advising protection for pregnant women with female sex partners who might have travelled to Zika endemic areas, though woman to woman transmission is not known till now.

The report stressed the need for further studies to determine the amount of time of virus survives in female genital tract.

The Aedes aegypti mosquitos still is the major source of infection.

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[1] http://www.cdc.gov/mmwr/volumes/65/wr/mm6528e2.htm?s_cid=mm6528e2_w

[2] http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2816%2930193-1/fulltext

[3] Dudley DM, Aliota MT, Mohr EL, et al. A rhesus macaque model of Asian-lineage Zika virus infection. Nat Commun 2016;7:12204

No evidence of congenital anomalies with Zika infection in third trimester.

The first outbreak of Zika virus occurred in South America occurred in Brazil in May 2015 subsequently in October Columbia confirmed 156 cases of Zika in 13 municipalities.[1]  Neurological abnormalities and other adverse pregnancy outcomes are associated with Zika infection in first and second trimester of pregnancy.

A recent surveillance report from the Colombian Instituto Nacional de Salud (INS) suggested that Zika infection in the last trimester of pregnancy does not cause any structural fetal defect. The report of this study was published in recent online edition of New England Journal of Medicine.[2]

A total of 65,726 cases of ZVD were reported in Colombia during the study period from August 9, 2015, through April 2, 2016. Out of these 2485 (4%) were found positive on RT-PCR assay. Zika infection was widespread in Colombia with 11,944 pregnant women affected, of which 1484 (12%) were confirmed on RT-PCR assay.

Out of 11,944 infected pregnant women, INS had complete data on for a subgroup of 1850 women correlating gestational age and the onset of symptoms of Zika infection. Out of these 1850 women, 616 women got infection in third trimester and in nearly 89-90% of these women no congenital anomalies were detected at birth.

The remaining women were infected in first and second trimester, so they still had ongoing pregnancy when the cut-off date of the study was reached. 

The number of cases reported in the study does not show the true magnitude of the Zika infection as the surveillance system does not include asymptomatic women or those women who do not go to healthcare provider.

The authors stressed the importance of healthcare providers in educating the patients about the vector and sexual mode of transmission of the Zika infection.

The INS and CDC jointly are implementing intensified surveillance in places with Zika infections to determine the full spectrum of disease in mother and infants in relation to gestational age at infection. 

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[1] http://www.who.int/emergencies/zika-virus/history/en/

[2] http://www.nejm.org/doi/full/10.1056/NEJMoa1604037#t=article

First baby born with ZIKA related microcephaly in Continental US

Tuesday saw the birth of first baby born with Zika related microcephaly at the  Hackensack University Medical Center, New Jersey. This is the second known case of a baby born with Zika-related birth defects in the United States. The first baby was born in Hawaii.

The mother is from Honduras and travelled to US to her relatives in hope of better medical care. Doctors in US believe that she contracted the disease probably in second trimester when she had fever and rash, which are symptoms of viral infection.

Her OBGYN  in Honduras suspected that she  had a baby with IUGR  and coordinated with CDC to send the samples for testing. As expected the results came back positive.

A last trimester ultrasound  revealed that baby had abnormalities including severe microcephaly, calcification of the brain, bowel problems and restricted growth.

Baby was delivered by emergency C-section and also suspected to suffer from other problems.

Honduras is one of half a dozen Latin American and Caribbean countries where abortion is not legal with no exceptions, not even to save a woman’s life, according to reproductive rights advocacy groups.

 As of May 12, 2016, the two Zika virus infection surveillance systems are monitoring 157 pregnant women in the U.S. states and 122 pregnant women in the U.S. territories with laboratory evidence of possible Zika virus infection.  That is a total of 279 pregnant women in U.S. states and territories who are followed closely as a part of national registry.

Till date almost 600 cases of Zika have been diagnosed in the US, but all sufferers have travelled to an infected country and none of them got infected in US.

According to the World Health Organization (WHO), women planning to become pregnant should wait at least eight weeks before trying to conceive if they or their partner live in or are returning from Zika virus hotspots.

The case comes at a time when Congress has yet to approve new funding to fight the virus, despite months of White House pressure. Congressional Republicans have rejected the White House’s request for $1.9 billion in new funds. 

References:

http://www.cdc.gov/media/releases/2016/s0520-pregnant-women-zika.html

http://www.cdc.gov/zika/hc-providers/registry.html

CDC Confirms the link between Zika infection and microcephaly.

Zika has been linked to microcephaly since Brazil reported a sudden increase in number of infants born with microcephaly in September 2015, but causation was not established. CDC today made an important announcement after careful review of all the possible evidence that Zika virus is a cause of microcephaly and other severe fetal brain defects.

The study is published online in the New England Journal of  Medicine today.

“This study marks a turning point in the Zika outbreak.  It is now clear that the virus causes microcephaly.  We are also launching further studies to determine whether children who have microcephaly born to mothers infected by the Zika virus is the tip of the iceberg of what we could see in damaging effects on the brain and other developmental problems,” said Tom Frieden, M.D., M.P.H., director of the CDC. “We’ve now confirmed what mounting evidence has suggested, affirming our early guidance to pregnant women and their partners to take steps to avoid Zika infection and to health care professionals who are talking to patients every day. We are working to do everything possible to protect the American public.”

The investigators examined the causality evidence in light of Shepard’s criterias, which is set of rules that must be satisfied before labeling  an agent being ‘ teratogenic’  and causing  congenital malformations. According to the Shepard’s criterias, causality is established when either criteria 1, 3, and 4 (rare exposure–rare defect approach) or criteria 1, 2, and 3 (epidemiologic approach) are fulfilled.

So, the relationship between Zika infection and microcephaly was termed casual under the rare exposure–rare defect approach as criteria 1, 3 and 4 were fulfilled:

1. Proven exposure must occur at a critical time during prenatal exposure: The microcephaly and other anomalies occur when the exposure occurs during first trimester or early second trimester. 
2. Careful delineation of clinical cases with the finding of a specific defect or syndrome: Infants with Zika infection do have a typical pattern which includes severe microcephaly, intracranial calcifications, and other brain anomalies, sometimes accompanied by eye findings, redundant scalp skin, arthrogryposis, and clubfoot which led the scientist to coin a term “Congenital Zika Syndrome.”
3. Rare exposure and a rare defect: This criterion was met because microcephaly is a rare defect with an incidence of 6 infants per 10,000 liveborn infants in the United States and infection in travelers who spent a limited amount of time in Brazil with active infection, constitute rare exposure for the patients.

Also supportive of causation is lack of alternative explanation for sudden increase in microcephaly cases in Brazil, French Polynesia and Colombia.

But, proving the causation is not enough in the fight against Zika infection. Many key questions are yet to be answered that have important implications.

CDC's director, Tom Frieden, MD said “We are launching further studies to determine whether children who have microcephaly born to mothers infected by the Zika virus is the tip of the iceberg of what we could see in damaging effects on the brain and other developmental problems," in a statement.

In addition to this researchers are also interested in knowing relative and absolute risk of infection and malformation. At present 1% to 29% of babies are born with microcephaly of all the mothers infected with the virus. They are also looking at other factors that modify the risk and severity of infections, such as gestational week at infection, additional morbidities and co-viral infection like Dengue fever.

CDC has not changed the travel warning or guidelines related to Zika infection after this publication.

Mark S. DeFrancesco, MD, MBA, President of the American College of Obstetricians and Gynecologists (ACOG), released the following statement regarding the U.S. Centers for Disease and Control and Prevention (CDC) paper addressing Zika virus “The message of the CDC paper underscores the importance of ongoing research into this outbreak. We once again encourage Congress to act swiftly to pass emergency funding to enhance our public health preparedness and enable America’s researchers to lead the charge in the development of a vaccine or treatment for this virus. Ongoing support for Zika virus research will protect American families and, indeed, families around the world."

References:

http://www.nejm.org/doi/full/10.1056/NEJMsr1604338?query=featured_home&

http://www.acog.org/About-ACOG/News-Room/Statements/2016/ACOG-Statement-on-the-CDC-Update-on-Zika-Virus

http://www.cdc.gov/media/releases/2016/s0413-zika-microcephaly.html

All about Zika virus infection.

Zika Virus was first isolated from rhesus monkeys  in Zika forest in Uganda in 1947, but was barely in news till now as it did not cause outbreak in humans.

The Zika virus is a flavivirus, part of the same family as yellow fever, West Nile, chikungunya and dengue. But unlike some of those viruses, there is no vaccine to prevent Zika or medicine to treat the infection.

The incubation period of Zika virus disease is not clear, but is likely to be a few days. The symptoms are similar to other arbovirus infections such as dengue, and include fever, skin rashes, conjunctivitis, muscle and joint pain, malaise, and headache. These symptoms are usually mild and last for 2-7 days. But, majority of patients with this infection have no or very little symptoms, causing it very difficult to track. They can, however, still transmit the disease if they are bitten by a mosquito that then bites someone else.

Transmission

The Vector for Zika is  Aedes mosquitoes (which usually bite during the morning and late afternoon/evening hours. On Tuesday CDC reported the first sexually transmitted case of Zika virus in Dallas, Texas.  Previously, there have been only two documented cases linking Zika to sex and isolated cases of spread through blood transfusion.

In addition, the CDC says there have been documented cases of virus transmission during labor( vertical transmission ) , blood transfusion, and laboratory exposure. While Zika has been found in breast milk, it's not yet confirmed it can be passed to the baby through nursing.

Diagnosis

According to CDC- During the first week of illness, Zika virus disease can often be diagnosed by performing reverse transcriptase-polymerase chain reaction (RT-PCR) on serum. Serology assays can also be used to detect Zika virus-specific IgM and neutralizing antibodies, which typically develop toward the end of the first week of illness. Plaque-reduction neutralization testing (PRNT) can be performed to measure virus-specific neutralizing antibodies to confirm primary flavivirus infections and differentiate from other viral illnesses.

World Health Organization Director-General Margaret Chan declared the current outbreak as  a public health emergency on February 1, 2016, with 24 countries involved from South and Central America and the Caribbean involved in the outbreak.

Courtesy: Vox.com

Zika is commanding attention worldwide because of connection between the virus and microcephaly.

According to CDC, in the past four months, microcephaly cases in Brazil rocketed to 3,500 from 147, the average for the same time last year (2014).  About 46 babies have died due to birth defects.

The link was first detected when Brazilian health authorities found traces of the Zika virus in a deceased infant born with microcephaly or in amniotic fluid of mothers delivering microcephalic infants.

The first confirmed cases of ZIKV infection in Brazil were reported in May 2015.

Transmission of the virus in Brazil is likely to have started several months before because the disease is new and mild, and could have been unrecognised or misdiagnosed, as dengue and chikungunya epidemics were ongoing.

Microcephaly caused due to any infection is usually caused by transplacental infections occurring early in pregnancy and is only detected during the second half of pregnancy or after birth.

The observed six months delay between the recognition of the transmission of ZIKV in May 2015, and the detection of an increase in microcephaly in November 2015, is therefore compatible with a temporal association between the two events.

Currently there is only ecological evidence of an association between the two events, due to sudden epidemic of microcephalic babies born and clustered around a specific time period. Researchers are still working to confirm the link — could it be something else that's causing the microcephaly?

On 13 January 2016, the Brazil Ministry of Health reported the detection of Zika virus genome, through the RT-PCR technique in four cases of congenital malformation in the state of Rio Grande do Norte. The cases correspond to two miscarriages and two full-term newborns (37 and 42 weeks respectively) who died in the first 24 hours of life. Tissue samples from both newborns were also positive for Zika virus by immunohistochemistry

Obstetrical providers should obtain a travel history from all pregnant women and use recent travel history to guide decisions about testing.  Testing is not indicated for pregnant women without a travel history to an area with Zika virus transmission.

Courtesy: Vox.com

Diagnosis in pregnant patients.

Zika virus RT-PCR can also be performed on amniotic fluid.  Other testing that can performed includes the following: 1) histopathologic examination and immunohistochemical staining of the placenta and umbilical cord, 2) Zika virus testing of frozen placental tissue and cord tissue, and 3) IgM and neutralizing antibody testing of cord blood.

Amniocentesis should be offered to pregnant women with recent travel to an area with Zika virus transmission, reporting 2 or more symptoms within two weeks of travel and a positive or inconclusive maternal serum test.  For pregnant women with recent travel to an area with Zika virus transmission and ultrasound findings of microcephaly or intracranial calcifications, amniocentesis may also be considered.

A positive Zika virus RT-PCR result from amniotic fluid would be suggestive of intrauterine infection.  This information would be useful for pregnant women and their healthcare providers to assist in determining clinical management (e.g., antepartum testing, delivery planning).  A negative Zika virus RT-PCR result from amniotic fluid may prompt a work up for other causes of microcephaly (e.g., other infections, genetic disorders).

There is currently no cure for the Zika virus. A number of institutions are scrambling to develop a vaccine, but it could take up to five years, as health experts called for new incentives for drug companies.

Meanwhile, American women who are pregnant have been advised to stay out of countries where the Zika virus is circulating. The CDC recommends consulting your doctor before your trip and following steps to prevent mosquito bites during the trip.

References:

http://www.cdc.gov/zika/index.html

http://www.who.int/csr/don/29-january-2016-zika-usa/en/

http://www.paho.org/hq/index.php?%20option=com_topics&view=article&id=427&Itemid=41484&lang=en