End of Zika in Sight?

Graduate Division

We’ve all heard about the Zika virus – its rapid rise in Brazil, the tragic birth defects, and the worldwide collaborations to combat it. Now Several UCSF labs are contributing key findings to the understanding of the Zika virus.

Zika became a strong concern of the World Health Organization (WHO) in late January 2016, due to its appearance at a new location (continental South America), its potential association with birth defects and Guillain-Barré syndrome, the widespread global distribution of its carrier, the Aedes mosquito, and lack of current diagnostic tests and treatments.

It was declared a “public health emergency of international concern” four days later.

The scientific understanding of Zika has improved in recent months. Scientists now know that if a mother is infected in the first trimester of pregnancy, her child will have up to a 13% chance of being born with microcephaly, a condition in which a child’s head is smaller than normal and the brain is smaller and/or incompletely developed.

Only about one out of five Zika infections is symptomatic, and non-symptomatic men can transmit Zika to their sexual partners, meaning that women of childbearing age in endemic and non-endemic regions may be at risk for fetal-harming infection.

UCSF labs that have recently contributed to the understanding of the Zika virus include Dr. Charles Chiu, Director of the UCSF-Abbott Viral Diagnostics and Discovery center, who led a team that used next-generation sequencing to find that Zika infection can co-occur with other viral infections.

This is important for physicians to know, because symptoms of Zika may be similar to or masked by other viral infections, indicating that multiple diagnostic approaches should be used.

Work from the lab of Dr. Arnold Kriegstein, director of the UCSF Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, found that stem cells in the developing brain and retina express the same receptor that allows Zika to infect skin cells.

This information may help narrow the search for a drug to prevent Zika from causing birth defects.

Additionally, Dr. Lenore Pereia’s group, who studies cell and tissue biology in the UCSF School of Dentistry, found that an old antibiotic, duramycin, may be able to prevent Zika transmission from mother to child. This antibiotic prevented infection of fetal and placental-derived cells in the laboratory.

Currently, no FDA-approved test or treatment for Zika exists. Scientists have been focusing on understanding more about the Zika virus so its infection of mothers and/or transmission to a developing fetus can be prevented. Many institutions and companies have been pursuing the development of a vaccine against Zika.

The role of a vaccine is to present an antigen to your body – an antigen is a molecule on or from within the microbe that the vaccine is trying to protect you against.

For example, this antigen could be a modified version of a virus, pieces of viral proteins, an inactivated bacterial toxin, or fragments of microbial DNA.

Macrophages, a type of white blood cell in your body, eat antigens and display small pieces of the antigens, called epitopes, on their surfaces. Foreign epitopes are recognized by lymphocytes, another type of white blood cell, which can destroy already infected cells (cytotoxic T cells) and stimulate production of neutralizing antibodies against the pathogen itself (B cells).

This stimulation of an immune response makes the body prepared to fight off a future infection from the microbe.

The urgent need for a Zika vaccine led researchers from many labs in the United States and Brazil on a collaborative venture spearheaded by the Viral Pathogenesis Section and Vaccine Research Center at the National Institutes of Health.

Their important findings, published on Science first release on September 22, explain how they evaluated the effectiveness of two different vaccine constructs at two different doses in the ability to neutralize Zika infection.

The authors chose to pursue a DNA vaccine for several reasons: 1) Flaviviruses, the family of viruses that Zika belongs to, have been successfully targeted with DNA vaccines in the past; 2) DNA vaccines are safe to give pregnant women and women of childbearing age; 3) Multiple epitopes can be quickly produced and screened; 4) DNA vaccines have a regulatory path that would allow faster progression to clinical trials.

The most potent neutralizing antibodies (NAbs) elicited by vaccines for flaviviruses are against an epitope in the third domain of the viral envelope protein.

First, the authors created two DNA constructs that mimic Zika virus by encoding sequences for some of its proteins. These constructs, when put into cells, should express Zika proteins that assemble into subviral particles (SVPs). SVPs elicit an immune response but will not form infectious virions, allowing the authors to study the immunogenicity of Zika without using the real virus and putting the researchers at risk for infection.

Vector VRC5283 expresses the first 93 amino acids of the Zika premembrane protein the entire envelope protein from the French Polynesian isolate of Zika. This strain is very similar, if not identical, to the strain in South America.

The authors added a signal sequence from another virus to increase SVP release. The second vector, VRC5288, uses the final 98 amino acids of Zika’s premembrane protein.

Both constructs successfully infected mammalian cells and created SVPs.

Next, the authors immunized two types of mice with VRC5283 or VRC5288. Serum collected from these mice contained antibodies that could bind to and neutralize Zika SVPs. The NAbs were present across a range of vaccine doses.

The favorable immune response elicited in mice led the authors to evaluate the immunogenicity of the DNA vectors in non-human primates, rhesus macaques.

The primates were treated with one or two doses of one or four milligrams of VRC5283 or VRC5288. The animals that received two doses of the DNA vaccines had significantly higher NAbs than those who received one, with no significant difference between VRC5283 or VRC5288.

The antibodies from both two-dose groups were able to bind and neutralize Zika SVPs equally well.

The primates were challenged with a live, Puerto Rican strain of Zika eight weeks after the first immunization. Quantitative PCR was used on daily blood samples to determine the number of Zika genome copies in the blood.

Viremia was prevented in 94% animals that received two four or one milligram doses of VRC5283 or two four milligram doses of VRC5288.

The authors successfully created DNA vaccines that elicited immune protection from Zika virus infection, and both will be evaluated in humans to determine what level of NAb production is necessary to prevent Zika infection in humans.

A Phase I clinical trial of VRC5283 is already underway.

This exciting development, if proven safe and effective, will still take many years to reach consumers.

Zika continues to be a time-sensitive concern, even in the United States, where on October 14 a new neighborhood in Miami was declared a Zika zone.