Zika antibody offers hope for a vaccine
A research team based at Rockefeller University has found a potent new weapon against Zika virus from the blood of infected people. The discovery may lead to new ways to fight the disease — even a vaccine.
In blood samples taken from subjects in Mexico and Brazil, scientists found antibodies — proteins made by the immune system — that block the virus from initiating infection. These antibodies appear to have been generated in response to an earlier infection by a related virus which causes dengue. One such antibody, called Z004, was particularly effective in neutralizing Zika.
"These antibodies could be very useful in the near future. One could envision administering Z004 to safely prevent Zika among pregnant women or others at risk of contracting the disease."
Davide F. Robbiani PhD, Research Associate Professor, Michel Nussenzweig Laboratory of Molecular Immunology, The Rockefeller University, New York, USA.
Robbiani and Leonia Bozzacco, a research affiliate in Charles M. Rice's lab, led the study, which appears in Cell on May 4. The team's detailed examination of the interaction between this antibody and the Zika virus also revealed a new potential strategy for developing a vaccine.
A mosquito-borne virus, Zika usually causes mild symptoms in those who contract it. But, dramatic and damaging effects can appear in a fetus being carried by an infected woman. Babies born to women infected during pregnancy are at risk of devastating neurodevelopmental abnormalities such as microcephaly. Today, the only way to prevent Zika is to avoid mosquito bites as there are no current vaccines or medical measures to prevent Zika. The virus that infects us travels in a spherical envelope studded with viral proteins. It latches onto a cell and forces its way inside. Facing this threat, our immune system generates antibodies that recognize the virus and act to stop the invasion.
Scientists set out to find antibodies tuned to attack part of Zika's envelope protein, which the virus uses to launch its attack. Through collaborators working in Pau da Lima, Brazil, and Santa Maria Mixtequilla, Mexico, they obtained blood samples from more than 400 people and collected shortly after Zika began circulating. Although, individual responses to the same pathogen can vary greatly, a deeper analysis of these more than 400 samples were winnowed down to six of the most promising antibodies — and revealed a surprise.
Five of the 400 samples contained nearly identical antibodies to the same viral species. A similarity suggesting these molecules were good viral fighters.
When the team examined these closely related antibodies' and how they performed against Zika, one stood out: Z004, an antibody from one Mexican volunteer's blood.
When given to mice vulnerable to Zika, the Z004 antibody protected the mice from developing a serious infection.
Pamela J. Bjorkman's lab at Caltech wanted to get a closer look at the interaction between the antibody and a fragment of the virus' protein envelope in order to determine the molecular structure that forms as the two interact.
The detailed maps Bjorkman's lab created of Zika and the antibody from the Mexican volunteer's blood, revealed that the antibody pinches a ridge on the virus when it binds to it.
Efforts to develop a vaccine have used all — or most — of the virus to stimulate an immune system response. But, researchers now believe it might be safer to use only a tiny fragment contained on this ridge. Zika isn't the only virus to sport a ridge. It is also present in viral envelopes of the dengue 1 virus, a close relative of Zika. Dengue 1 is one of four types of dengue with a ridge remarkably similar to Zika's.
Z004 neutralized dengue 1 as well as Zika viruses.
Reviewing Brazilian samples collected six months before Zika arrived, revealed prior dengue 1 infections in some of the Brazilians — and an explanation for why certain immune systems fared better against Zika.
"Even before Zika, their [Brazilian] blood samples likely had antibodies that could interact with this same spot on the protein envelope. It appears that, much like a vaccine, dengue 1 can prime the immune system to respond to Zika."
Margaret R. MacDonald Phd, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
• Pre-existing antibodies to DENV1 correlate with high ZIKV neutralizing responses
• Antibodies to the EDIII lateral ridge correlate with serum neutralization of ZIKV
• Recurrent VH3-23/VK1-5 antibodies to the EDIII potently neutralize ZIKV and DENV1
• The structures of VH3-23/VK1-5 antibodies with the EDIIIs of DENV1 and ZIKV were solved
Antibodies to Zika virus (ZIKV) can be protective. To examine the antibody response in individuals who develop high titers of anti-ZIKV antibodies, we screened cohorts in Brazil and Mexico for ZIKV envelope domain III (ZEDIII) binding and neutralization. We find that serologic reactivity to dengue 1 virus (DENV1) EDIII before ZIKV exposure is associated with increased ZIKV neutralizing titers after exposure. Antibody cloning shows that donors with high ZIKV neutralizing antibody titers have expanded clones of memory B cells that express the same immunoglobulin VH3-23/VK1-5 genes. These recurring antibodies cross-react with DENV1, but not other flaviviruses, neutralize both DENV1 and ZIKV, and protect mice against ZIKV challenge. Structural analyses reveal the mechanism of recognition of the ZEDIII lateral ridge by VH3-23/VK1-5 antibodies. Serologic testing shows that antibodies to this region correlate with serum neutralizing activity to ZIKV. Thus, high neutralizing responses to ZIKV are associated with pre-existing reactivity to DENV1 in humans.
Nussenzweig is the Zanvil A. Cohn and Ralph M. Steinman Professor and Rice is the Maurice R. and Corinne P. Greenberg Professor in Virology.
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