Antibodies created during a viral infection or in response to a vaccine help to prevent reinfection with that specific virus but can, in some cases, worsen infections by similar ones. This phenomenon, called antibody-dependent enhancement (ADE), is particularly problematic for the related flaviviruses Zika and dengue. Researchers are therefore developing vaccination strategies to avoid the issue, and results from the latest incarnation tested in mice were reported yesterday (May 11) in Cell Reports

“In the vaccine field, people have been focused on eliciting antibody responses, and that’s great of course, but . . . T cells are also important in mediating protective immunity,” says immunologist Sujan Shresta of the La Jolla Institute for Immunology who works on Zika and dengue vaccination strategies and has developed her own T cell–boosting vaccine but was not involved in the new study. Her progress together with yesterday’s report “really challenges the dogma,” that antibodies are the most important component of a vaccine response, she says, “and now I think the field really has to take note and look into incorporating these new findings in developing next-generation dengue and Zika vaccines.”

There are two arms to the adaptive immune response to a virus: B cells, which recognize the virus outside cells and produce antibodies to bind and neutralize it, and T cells, which detect infected cells via the presentation of viral antigens on the cells’ surfaces and promptly kill those cells. In this way, the two arms react to different parts of the virus. The B cells, for example, tend to spot structural proteins on the surface of the virus, while the T cells home in on nonstructural viral components produced within infected cells.

This two-pronged response works well for dealing with all manner of viral invaders, but it seems that while the antibodies created during the first infection are a perfect fit for the original virus, the less-specific interaction with a subsequent, related invader actually helps that virus enter cells. “The virus is being very clever. It’s using the immune response to . . . help itself,” says Shresta.

Viruses of the flavivirus family, such as Zika and dengue, both transmitted to humans via the bites of infected mosquitoes, are particularly adept at this antibody exploitation. Indeed, a past infection with Zika increases the severity of a subsequent infection with dengue, and even vaccines against certain dengue serotypes—there are four in all—can worsen infections with others.

See “Zika Infection Increases Risk of Severe Dengue Fever

“To address this concern, our approach was to develop a vaccine that does not induce antibodies but induces only [cytotoxic T cells] that can kill virus-infected cells,” explains study author Liang Qiao of Loyola University Chicago in an email to The Scientist.

The team achieved this by creating a DNA-based vaccine that encodes the nonstructural Zika protein NS3, which is known to elicit a strong T cell response in humans and is unlikely to induce antibodies, certainly not ones that could be exploited in future infections. That’s because “[o]nly antibodies directed at the structural proteins and specifically Envelope protein can cause ADE,” explains immunologist Ashley St. John in an email. St. John is based at Duke-NUS in Singapore and did not participate in the research.

To maximize the induction of a T cell response, Qiao’s team also included genetic code that would result in the addition of a degradation signal to NS3. Because antigens presented to T cells are generated by the cell’s degradation pathway, the signal would help to get the NS3 fragments to where they are needed.

“This is quite an interesting approach,” Marion Koopmans, a virologist at Erasmus University Medical Center in the Netherlands who was not involved in the study, writes in an email to The Scientist. “Because of the way this protein was offered, it was targeted directly to the parts of the cell that process it and offer it to the immune system, triggering a T cell response,” she says.

The team showed that its DNA vaccine was transcribed, translated, and degraded quickly inside cells, that it did not induce detectable anti-NS3 or anti-Zika antibodies in mice, and that it did not enable ADE of cells in culture.

See “COVID-19 Vaccine Researchers Mindful of Immune Enhancement

They then tested the vaccine’s protective effects. Two shots of the vaccine improved the survival of mice that were later infected with Zika compared with unvaccinated animals. Furthermore, in pregnant mice, the vaccine protected the animals’ uteri and fetuses from significant viral infection and damage.

The team showed that this protection of mice and their fetuses was lost if the animals’ T cells were depleted after vaccination. This suggests that cytotoxic T cells “alone may be protective against an infectious agent,” writes Qiao.

The risk of inducing antibodies that may enhance disease in flavivirus vaccines is a headache, and I do think this is a very interesting angle.

—Marion Koopmans, Erasmus University Medical Center

Last year, Shresta’s team also produced an NS3-based vaccine that stimulated a T cell response without antibodies. Her vaccine was RNA-based and similarly protected mice from lethal Zika infection and fetal mice from growth impairment when the mother was exposed to the virus.

“It’s really nice to see validation,” she says. “It’s important . . .  to have two different approaches, two different research groups finding the same thing.”

Both Shresta’s and Qiao’s research was in mice, and while flavivirus infection and ADE seem to work similarly in mice and humans, “this work is still at a proof-of-concept stage,” writes St. John. 

“The mouse model is somewhat artificial, and it remains to be seen if this would work in humans,” adds Koopmans. Nevertheless, “the concept is quite intelligent. The risk of inducing antibodies that may enhance disease in flavivirus vaccines is a headache, and I do think this is a very interesting angle. It is far away from human application, but it is great to see some good basic science tackling an important public health concern.”

Although, “currently, no clinical trials are planned” with the vaccine, says Qiao, the urgency for a Zika vaccine is pressing. “Many people might think that Zika virus is no longer a threat. However, there are still hot spots, especially in tropical countries,” he says. “Because the virus may cause fetal damages, a vaccine is needed.” 

F. Gambino Jr. et al., “A vaccine inducing solely cytotoxic T lymphocytes fully prevents Zika virus infection and fetal damage,” Cell Rep, doi:10.1016/j.celrep.2021.109107, 2021.



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