In a study published in Nature Communications in August 2023 presents early findings for a “cutting-edge” vaccine candidate developed at QIMR Berghofer. This article suggests that the vaccine candidate, targeting Epstein-Barr virus (EBV), achieved “robust” and “persistent” immune responses and is in a good position to progress to “future clinical assessment”.
EBV
EBV is a herpesvirus, carried by at least 95% of the adult population across the world. It usually lies dormant after infection in early childhood but can cause severe illness in some people. The authors state that, while acquisition of EBV infection in adolescents or young adults is “often asymptomatic”, the development of “symptomatic infectious mononucleosis” (IM) occurs for some.
IM is considered a “major risk factor” for the later development of multiple EBV-associated diseases such as multiple sclerosis (MS), an “incurable neurological disease” that causes the immune system to mistakenly attack the protective coating around nerves. EBV is also considered the “primary etiological agent” associated with multiple lymphoid and epithelial cancers. In 2022 a study concluded that EBV is likely the leading cause of MS. Thus, prevention of EBV-associated IM could potentially prevent MS in the future.
MS affects around 3 million people around the world, including over 33 thousand Australians. The NHS suggests that it is “most commonly diagnosed” in people between the ages of 20 to 40 but can develop at any age. It is roughly 2 to 3 times more common in women than men. It causes symptoms such as fatigue, impaired mobility, pain, or brain fog.
Research at QIMR Berghofer
Although “several” prophylactic and therapeutic approaches are being pursued, there has been no licensed medical intervention for EBV infection. The goal, therefore, of “optimal” vaccines to control primary and latent infection would be induction of both humoral and cellular immune responses. These would target viral glycoproteins, lytic and latent antigens, and latent membrane proteins.
The article suggests that subunit vaccination would be an “attractive strategy for this purpose”, but full-length EBV latent proteins can “trigger oncogenesis by blocking apoptosis, promoting genomic instability, and supporting uncontrolled cell proliferation”. This “limits” their use as vaccine immunogens. Furthermore, “polyvalent strategies requiring manufacturing and co-formulation of numerous protein immunogens required to induce the necessary breadth of immunity” are challenged by cost and manufacturing complexity.
Thus, a strategy was developed to “specifically target multiple latent and lytic EBV protein epitopes”, overcoming the limiting factors for use in vaccine formulation. Through “extensive mapping” of human CD8+ T cell epitopes from EBV antigens by multiple groups, the team was able to design a polyepitope vaccine immunogen (EBVpoly) that incorporates multiple CD8+ T cell epitopes into an engineered protein immunogen.
Positive results
QIMR Berghofer’s Professor Rajiv Khanna AO led the development of the vaccine and is collaborating with Atara Biotherapeutics, developers of ATA188, a cell-based therapy targeting the cause of MS. The vaccine may work in combination with this therapy, and Professor Khanna is encouraged by the results of the study.
“Other vaccine efforts have focused on inducing neutralising antibodies against the virus, which blocks infection of immune B cells during primary acute infection. But EBV in its latent state hides inside B cells, turning them into tiny virus factories ready to divide and spread whenever our immune defences are down.”
So, what does this vaccine offer in response? Professor Khanna thinks that for some people, EBV-infected B cells travel to the brain to “cause inflammation and damage”.
“If we can prevent this at an early stage of infection then the infected B cells can’t go on to cause the development of a secondary disease like MS.”
The study suggests that the vaccine induced “potent and persistent” humoral and cellular immunity in pre-clinical models. The immune response also eliminated or greatly delayed the growth of EBV-positive lymphoma tumour cells in laboratory models. After so many years of research, lead author Dr Vijayendra Dasari of QIMR Berghofer is “really proud” to see the work come together. The vaccine is “now heading towards the next important stages of development”.
“The data presented here clearly demonstrate that EBV protein subunit vaccine formulated with AMP-CpG can generate robust virus-specific cellular and humoral immunity, which is persistent and capable of rapid expansion upon recall through exposure to EBV antigens. These studies provide an important platform for future clinical assessment of this vaccine formulation in human volunteers.”
Collaboration with Elicio and Atara
The research team behind the study incorporated biotechnology company Elicio Therapeutics. Dr Peter DeMuth, co-author and Chief Scientific Officer of Elicio, commented that the Amphiphile vaccine adjuvant, AMP-CpG, was useful in taking the vaccine to the lymph nodes for immune response activation. He is “excited” by the data.
“Pre-clinical validation suggests that it not only demonstrates an exciting opportunity for a potential EBV vaccine, but also validates the utility of the AMP platform to improve lymph node immune activation resulting in potent immune responses against historically challenging pathogens.”
The research was funded by Atara Biotherapeutics, also supporting QIMR Berghofer with the development of another EBV-vaccine composition with a different adjuvant.
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