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Tick-Borne Encephalitis Virus More Vulnerable to Less Common Antibodies

A study of the human antibody response to the tick-borne encephalitis (TBE) virus reveals that it is dominated by ineffective antibodies. Occasionally, however, a few antibodies appear that are extremely potent. Now that potent antibodies have been discovered, and their structures determined, the prospects for targeting the TBE virus suddenly look much better. TBE, which still beyond the reach of any specific treatment, could become treatable, and better vaccines could be developed.

Details appeared April 8 in the Journal of Experimental Medicine, in an article titled, “Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease.” The article described how scientists based at Rockefeller University examined nearly 800 antibodies obtained from individuals who had recovered from TBE virus or had been vaccinated to prevent infection. The article also reported on “the molecular properties of human anti-TBEV antibodies with exceptional neutralizing potency and breadth that are effective in protection and early therapy in mice.”

Closely related anti-envelope domain III (EDIII) antibodies were found in both infected and vaccinated individuals. However, the most potent neutralizing antibodies were found only in individuals who recovered from natural infection.

“You’d expect the most prevalent antibodies to be the absolute best, but that is not what we found in TBE,” said Marianna Agudelo, a researcher in the in the laboratory of Rockefeller’s Michel C. Nussenzweig. “This may explain how the virus tricks the immune system, misdirecting it into producing inferior antibodies.”

The most potent antibodies, designated VH3-48, turned out to be best at neutralizing laboratory-grown varieties of the TBE virus, as well other tick-borne flaviviruses including the Langat, Louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses.

“Structural analysis revealed a conserved epitope near the lateral ridge of EDIII adjoining the EDI–EDIII hinge region,” the authors of the JEM article wrote. “Prophylactic or early therapeutic antibody administration was effective at low doses in mice that were lethally infected with TBEV.”

Tick-borne encephalitis is a disease just as nasty as it sounds. Once bitten by an infected tick, some people develop flu-like symptoms that resolve quietly but leave behind rampant neurological disease—brain swelling, memory loss, and cognitive decline.

Cases of TBE are on the rise in Central Europe and Russia with some 10,000 incidents reported each year. The related Powassan virus is emerging in the United States.

There is no cure for TBE. The vaccines that are currently available require three doses spaced over two years and only provide about five years of protection before a booster shot is required.

Next-generation vaccines built around coaxing the body into producing the rare VH3-48 antibody could be more potent, require fewer booster shots, and also prove protective against a number of tick-borne viruses.

“A vaccine like this would not just be more elegant, but also better focused,” said Nussenzweig, the senior author of the JEM study and head of the Laboratory of Molecular Immunology at Rockefeller. “Now that we have the structures of these antibodies, we know what to target in order to design more effective vaccines.”

Broadly neutralizing antibodies may also provide the first specific treatment for TBE. Nussenzweig, Agudelo, and colleagues found that mice infected with TBE recover after receiving antibody therapy, although it remains to be seen if this finding will translate to humans.

“The next step is a clinical trial with the antibodies,” added Nussenzweig, who is also the Zanvil A. Cohn and Ralph M. Steinman Professor at Rockefeller. “Perhaps in Europe, where there are many cases, [a clinical trial will determine] whether we can ameliorate the symptoms of those suffering from encephalitis.”

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