Vaccine development

By definition, vaccines are preparations that protect from a certain infectious microorganism. Most vaccines are composed of an attenuated or killed form of this microorganism or one of its proteins. Most vaccines are used prophylactic, i.e. to prevent a future infection or to alleviate its symptoms. Vaccines against microbes associated with forms of cancer (like HPV, HBV, EBV and Helicobacter pylori) that protect from developing the disease are also referred to as ‘cancer vaccines’.

Vaccines are also among the most cost-effective drugs if the risk to develop a certain disease without being vaccinated is relatively high. For EBV two groups of individuals can be defined that fulfill this prerequisite and that, consequently, would benefit most from an effective EBV vaccine:

  1. Adolescents and adults who had not been in contact with the virus previously. These people are at risk to develop infectious mononucleosis upon infection, an acute infectious disease and also an independent risk factor for certain forms of lymphoma later in life.
  2. EBV-negative immuncompromised patients like those undergoing organ or bone marrow transplantation. They are at extremely high risk to develop EBV-associated lymphoproliferative diseases which could most presumably be prevented by vaccination, and thus seroconversion, prior to immunosuppression.

Coexistence of primates and there herpes viruses for millions of years has allowed the viruses to develop sophisticated strategies to evade the host’s immune responses and to persist for the life of the individual. Thus, it seems unlikely that herpes viral vaccines will achieve sterilizing immunity and the aim of vaccination is prevention of disease rather than infection.

EBV vaccine candidates that currently are or had been under development so far, rely on the administration of a single EBV protein or fragments thereof, either in the form of synthetic peptides or via gene vectors such as genetically altered vaccinia viruses. The EBV protein mostly used in these formulation is gp350, a glycosylated envelop protein that mediates binding of virus particle to CD21 on target cells. gp350-vaccines induce specific antibodies and probably also relieve the symptoms of infectious mononucleosis. However, since gp350 is normally not expressed on EBV-infected tumor cells, they will not prevent the development of cancer.

A virus-like particle based EBV vaccine

Live attenuated vaccines are the most effective vaccines known. They provoke immune responses of the cellular and humoral immune system and evoke long-lived immune responses. Attenuation of viruses is normally obtained by serial passages on permissive cells that support autonomous virus production. Unfortunately, a spontaneous lytic system is not known for EBV making the virus recalcitrant to classical methods of attenuation. Moreover, EBV is a tumor virus and several viral genes can contribute to tumor genesis.

We have therefore decided to develop an EBV vaccine candidate on the basis of virus-like particles (VLPs). VLPs contain most viral structural proteins, morphologically resemble the virus and thus induce a broad range of virus-specific immune responses like neutralizing antibodies in immunized individuals. But VLPs lack the viral genome and therefore are non-infectious.

We have established a technology to produce EBV-VLPs containing various viral proteins and RNA molecules. These VLPs have the same tropism as EBV, i.e. they efficiently interact with human B cells, reactivate EBV-specific immune responses in EBV-positive individuals, and induce the generation of EBV-specific antibodies and T cells in immunized animals including immune responses against viral proteins that are expressed in EBV-associated cancer. (more)