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A New Vaccine for EBV, the World’s Most Successful Virus

The Epstein-Barr virus.
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A study details a new vaccine against the Epstein Barr virus (EBV), one of the world’s most successful infectious agents and a cause of cancer and multiple sclerosis. The research is published in Nature Communications.

A silent and successful virus

The coronavirus pandemic showed how an infectious virus could shut down society. While the steps governments took to control the virus will be debated in public health for decades to come, in March 2020 the need to do something – anything – to stop the spread of a virus that could infect the whole human race was inescapable.

But before SARS-CoV-2 captured headlines and reshaped our society, another virus had already established itself as a master infector of the human race: EBV. A member of the herpesvirus family, EBV has, without any of the panic produced by SARS-CoV-2, come to infect more than 95% of the human population. One reason for the relaxed response to the mass spread of EBV is that the disease it causes, infectious mononucleosis or mono, pales in comparison to the effects of COVID-19. As EBV is so successful, most people are infected in their young adulthood, an age group in which mono causes nearly 1 in 10 sore throats.

Once the fever and swollen neck caused by mono resides, EBV doesn’t go away. It nests in a subset of our immune cells called B cells. It then stays there – for life. B cells are an essential component of our immune system – orchestrating antibody responses to other infections – meaning we can’t just excise these infected cells. Instead, the body settles into an uneasy truce, where infected cells are marshaled by another immune cell type – T cells – that stop the infection from spreading. But a growing understanding of how EBV works suggests that the impact of letting a virus live in our body for life may be greater than we realized.

“EBV is associated with multiple lymphoid and epithelial cancers such as Burkitt lymphoma (BL), Hodgkin lymphoma (HL), B-, T-, natural killer cell lymphoma, post-transplant lymphoproliferative disorder (PTLD), gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC). In fact, it is estimated that EBV is responsible for approximately 265,000 new cases of cancers and 164,000 cancer deaths globally per year,” explain Vijayendra Dasari and Rajiv Khanna, authors of the new paper and researchers at the Berghofer Medical Research Institute’s Centre for Immunotherapy and Vaccine Development in Brisbane, Australia.

A seismic paper published last year also showed that EBV infection is required for people to develop multiple sclerosis (MS). A vaccine against EBV could open the possibility of massively reducing the incidence of these diseases in future generations.

Complex virus, complex vaccine

A vaccine against EBV has proved elusive to researchers; the virus hasn’t become so successful by being easy to hunt. It’s a complex agent that shifts over its life cycle, making it hard to aim a vaccine at any one viral target. An effective vaccine, say Dasari and Khanna, will need to “induce both antibody and cellular immune responses against multiple viral proteins.”

One approach that might usually serve this purpose, subunit vaccination, incorporates whole sections of viral protein into a vaccine’s structure, helping the immune system better recognize and neutralize the real virus later on. But in addressing EBV, subunit vaccination is a non-starter; the virus is so oncogenic that its use in a vaccine might increase cancer risk in the vaccinated.

Instead, the team designed a vaccine using an innovative approach that matches the complexity and ingeniousness of the virus itself.

Rather than including whole proteins or protein subunits in their vaccine, the team instead constructed their vaccine using epitopes – small sequences of amino acids that activate an immune response. By using this more compact approach, the team was also able to add multiple epitopes onto a vaccine “chain” – incorporating 20 EBV epitopes in total. Each epitope targets one of the proteins that EBV expressed at different stages of its life cycle. Dasari and Khanna hope that when the human immune system is exposed to the vaccine, it will generate cells that can respond to EBV in both its acute and latent phases.

Dasari and Khanna’s team also designed a novel adjuvant – a vaccine ingredient that enhances its power and targeting ability. This adjuvant, they say “allows trafficking of vaccine antigens directly to lymph nodes which are the primary sites for induction of both humoral and cellular immune responses.”

Genetically altered mice

The power and precision of the new vaccine have been demonstrated in a series of experiments using mice genetically altered to feature a human-like immune system. Vaccinated mice produced a robust immune response against EBV that lasted for more than seven months – a serious chunk of time in the roughly two-year mouse lifespan.

EBV increases the risk of developing an immune cell cancer called B cell lymphoma. While unvaccinated mice injected with cancerous B cells quickly developed tumors, the cancer’s spread was largely neutralized in vaccinated mice.

Dasari and Khanna’s research remains at an early stage, and future work will have to assess how well the vaccine can boost the human, rather than mouse, immune system. But the significant and silent burden of EBV infection shouldn’t be ignored any longer, say the authors.

While the vaccine has been designed to treat future generations not yet infected with EBV, the team plan to see whether it can have uses in the here and now. “It will be interesting to see if this vaccine can also help to protect EBV-infected individuals from future emergence of EBV-associated diseases such as MS,” they add.

Reference: Dasari V, McNeil LK, Beckett K et al. Lymph node targeted multi-epitope subunit vaccine promotes effective immunity to EBV in HLA-expressing mice. Nat Comms. 2023; 14:4371. doi: 10.1038/s41467-023-39770-1