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.

Keywords:

• controlled replication
• heat-activated and ligand-activated gene switches
• HSV
• regulation of replication-essential genes
• replication-competent virus
• vaccination
• viral immunization agent

Financial & competing interests disclosure

R Voellmy is the founder and a principal of HSF Pharmaceuticals SA, a company which has been supporting sponsored research at the institutions with which the co-authors are associated, including research conducted in the co-authors laboratories. N Vilaboa is supported by Program I2 from Comunidad de Madrid (Spain) and by grant PI12/01698 from Fondo de Investigaciones Sanitarias (FIS, Spanish Ministry of Economy and Competitiveness, MINECO, Spain). DC Bloom is supported by grants from the National Institutes of Health and an award from the UF Research Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Immunization to prevent or treat disease has a long history and was practiced before disease-causing microbes were identified and before even the most basic features of the immune system had become known. The pioneering work of Jenner, Pasteur et al. inaugurated the age of vaccination. In this approach to immunization, which has become the predominant approach practiced, a subject is inoculated with an attenuated live or killed form (or a fraction/subunit thereof) of a disease-causing microbe that does not cause significant disease with the goal of inducing protective immunity to subsequent infection by the disease-causing form of the microbe. The same approach is also practiced to induce a therapeutic immune response in a subject already infected with a disease-causing microbe.

• While vaccination has been hugely successful overall, highly effective prophylactic or therapeutic vaccines still have not been developed for a number of infectious diseases, including some that are of global concern, including influenza, HIV, TB, malaria and herpetic disease. Exploration of new immunization approaches appears warranted.

• We discuss an alternative concept for immunization that arguably may induce stronger and more complete immune responses than attenuated or killed vaccines. In this approach, a disease-causing virus would be genetically modified to subject two (or more) replication-essential genes to the control of a gene switch that is activated by non-lethal heat in the presence of a drug-like compound. Upon inoculation of a subject with such a replication-competent controlled virus and compound, one round of replication of the virus would be triggered by administration of an appropriate heat dose to the site of inoculation. One or more additional rounds may be induced subsequently.

• Replication would be confined strictly to the heated region. No replication would occur in the absence of activation. Live or killed viral vaccines are necessarily replication-impaired or replication-incompetent and express at most an incomplete set of antigens. In contrast, upon activation, replication-competent controlled virus would replicate in the inoculation region with an efficiency approaching that of the respective disease-causing virus and express a full set of antigens.

• A replication-competent controlled virus may not only be utilized to elicit immune responses to its own antigens, but may also serve as a vector for the expression of heterologous antigens or as a device for controlling replication of a co-infecting microbe.

• We suggest that a replication-competent controlled virus could be a safe immunization vector. Because it will be stringently and deliberately regulated, replication-competent controlled virus may be employed with immunocompromised including elderly subjects, in which use of an attenuated viral vaccine would raise concerns.

Notes