Identification of GLA/SE as an effective adjuvant for the induction of robust humoral and cell-mediated immune responses to EBV-gp350 in mice and rabbits

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• 作者：Darren S. Heeke^a ; Rui Lin^a ; Eileen Rao^b ; Jennifer C. Woo^b ; Michael P. McCarthy^c ; Jason D. Marshall^c ; ^{marshallj@medimmune.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AIM ; acute infectious mononucleosis ; EBV ; Epstein&ndash ; Barr virus ; GLA ; glucopyranosyl lipid A ; GLA-AF ; GLA-aqueous formulation ; IM ; intramuscular ; nAbs ; neutralizing antibodies ; SE ; stable emulsion
• 刊名：Vaccine
• 出版年：2016
• 出版时间：17 May 2016
• 年：2016
• 卷：34
• 期：23
• 页码：2562-2569
• 全文大小：1781 K

文摘

Childhood infection with Epstein–Barr virus (EBV) is often asymptomatic and may result in mild flu-like symptoms, but exposure during adolescence and young adulthood can lead to acute infectious mononucleosis (AIM) with a pathology characterized by swollen lymph nodes, sore throat, and severe fatigue lasting weeks or months. A vaccine targeting the envelope glycoprotein gp350 adjuvanted with aluminum hydroxide complexed with the TLR4 agonist monophosphoryl lipid A (MPLA) achieved a 78% reduction in AIM incidence in a small phase II trial of college-age individuals, but development of this vaccine was halted by the manufacturer. Here, we report the evaluation in mice and rabbits of an EBV-gp350 vaccine combined with an adjuvant composed of the synthetic TLR4 agonist glucopyranosyl lipid A (GLA) integrated into stable emulsion (SE). In mice, GLA/SE-adjuvanted gp350 generated high IgG titers (both IgG1 and IgG2a/c subtypes), elevated EBV-neutralizing antibody titers, and robust poly-functional anti-gp350 CD4⁺ T cell responses. In addition, GLA/SE routinely demonstrated superior performance over aluminum hydroxide in all immunological readouts, including induction of durable neutralizing antibody titers out to at least 1 year post-vaccination. Both components of the GLA/SE adjuvant were found to be required to get optimal responses in both arms of the immune response: specifically, SE for neutralizing antibodies and GLA for induction of T cell responses. Furthermore, this vaccine also elicited high neutralizing antibody titers in a second species, rabbit. These promising results suggest that clinical development of a vaccine comprised of EBV-gp350 plus GLA/SE has the potential to prevent AIM in post-adolescents.