A novel approach for addressing diseases not yielding to effective vaccination? Immunization by replication-competent controlled virus

Abstract

Vaccination involves inoculation of a subject with a disabled disease-causing microbe or parts thereof. While vaccination has been highly successful, we still lack sufficiently effective vaccines for important infectious diseases. We propose that a more complete immune response than that elicited from a vaccine may be obtained from immunization with a disease-causing virus modified to subject replication-essential genes to the control of a gene switch activated by non-lethal heat in the presence of a drug-like compound. Upon inoculation, strictly localized replication of the virus would be triggered by a heat dose administered to the inoculation site. Activated virus would transiently replicate with an efficiency approaching that of the disease-causing virus and express all viral antigens. It may also vector heterologous antigens or control co-infecting microbes.

Replication-Competent Controlled Herpes Simplex Virus

“…Ligand-independent activation of PR can occur and involves enhanced phosphorylation of PR or a coactivator interacting with PR activation function 1 (AF-1) or AF-2 (see reference 7 and references cited therein). The PR sequence in GLP65 lacks all PR AFs, the unique PR sumoylation site, and all known PR sites whose phosphorylation can enhance PR activity (7,44). Hence, ligand-independent activation should not occur and, to the best of our knowledge, has not been observed during the many years that this transactivator has been tested in diverse animal models.…”

Immunization by Replication-Competent, Controlled Viral Pathogen ? A Novel Approach Worth Exploring for Diseases Refractory to Effective Conventional Vaccination?

“…Based on these considerations and findings, we hypothesized that a genetically altered viral pathogen that can be transiently activated in an inoculation site region to (locally) replicate with an efficiency approaching that of the corresponding wild type agent would be a superior immunization agent to a conventional vaccine [9]. Replication is understood here as propagation of the agent.…”

“…We suggested that adequate safety from inadvertent activation, whether caused by exceptional circumstances (e.g., ischemia, intoxication, etc.) or a recombination event, could come from using a dual-responsive gene switch for controlling at least two replication-essential genes of a viral pathogen that is to be used as an immunization agent [9]. Dual-responsive gene switches that are activated by a combination of heat and a small-molecule regulator (SMR) were described previously and are known to stringently control expression of target genes both in vitro and in vivo [13][14][15].…”

“…Many studies have addressed this question for HSV, our preferred backbone for controlled virus construction (cited in ref. 9). The prevailing answer is that pre-existing immunity has little effect or only relatively minor effects on immune responses to HSV-delivered antigens or on anti-tumour efficacy of oncolytic HSV.…”

Immunization by replication-competent controlled herpesvirus vectors

“…We hypothesized that a virus vector that could replicate in a controlled fashion with nearly the same efficiency as the respective wildtype virus (referred to herein as “replication-competent controlled virus vector”) would induce an even more potent and complete immune response to itself or an expressed heterologous antigen than a corresponding attenuated vector (26). Our hypothesis is in part based on the rational expectation that an efficiently replicating virus will produce a stronger inflammatory response than an attenuated virus, which inflammatory response will result in a potent activation of the innate immune system and, consequently, in strong and lasting B and T cell responses (27).…”