Herpes Simplex Viruses Whose Replication Can Be Deliberately Controlled as Candidate Vaccines

Abstract

Over the last few years, we have been evaluating a novel paradigm for immunization using viruses or virus-based vectors. Safety is provided not by attenuation or inactivation of vaccine viruses, but by the introduction into the viral genomes of genetic mechanisms that allow for stringent, deliberate spatial and temporal control of virus replication. The resulting replication-competent controlled viruses (RCCVs) can be activated to undergo one or, if desired, several rounds of efficient replication at the inoculation site, but are nonreplicating in the absence of activation. Extrapolating from observations that attenuated replicating viruses are better immunogens than replication-defective or inactivated viruses, it was hypothesized that RCCVs that replicate with wild-type-like efficiency when activated will be even better immunogens. The vigorous replication of the RCCVs should also render heterologous antigens expressed from them highly immunogenic. RCCVs for administration to skin sites or mucosal membranes were constructed using a virulent wild-type HSV-1 strain as the backbone. The recombinants are activated by a localized heat treatment to the inoculation site in the presence of a small-molecule regulator (SMR). Derivatives expressing influenza virus antigens were also prepared. Immunization/challenge experiments in mouse models revealed that the activated RCCVs induced far better protective immune responses against themselves as well as against the heterologous antigens they express than unactivated RCCVs or a replication-defective HSV-1 strain. Neutralizing antibody and proliferation responses mirrored these findings. We believe that the data obtained so far warrant further research to explore the possibility of developing effective RCCV-based vaccines directed to herpetic diseases and/or diseases caused by other pathogens.

Insights into the Novel Therapeutics and Vaccines against Herpes Simplex Virus

“…Similar to the live-attenuated mechanism, this mechanism involves variations in terms of killed virus vaccination to avoid the risk of reactivation of viruses in subjects. Traditionally, phenol chemicals and UV light treatments have been used for this purpose, but other methods of viral inactivation have also been used more recently [ 79 , 80 ]. This approach is used as immunotherapy but remains underrated as it only provides little help to regress the viral infection, which is a property of natural infection.…”

“…This approach is used as immunotherapy but remains underrated as it only provides little help to regress the viral infection, which is a property of natural infection. Recent advances have been made, and some newer studies are in progress that use sonication, chemicals, radiation, UV light, formaldehyde treatment, or their combination to cause viral death [ 80 , 81 , 82 ]. Moreover, experiments are performed by regulating the dosage amount, time, route, and number of administrations and combination with adjuvants to check the efficacy.…”

“…Moreover, experiments are performed by regulating the dosage amount, time, route, and number of administrations and combination with adjuvants to check the efficacy. However, further work is necessary to deduce the efficiency of this vaccination method [ 80 , 83 ].…”

Selection of Analytical Technology and Development of Analytical Procedures Using the Analytical Target Profile

“…Virus-based vaccines and antigens produced using recombinant DNA technology represent an important part of the vaccines under development and available on the market . A refinement of the recombinant DNA technology consists in delivering the gene of interest directly into the host and in using the host cell machinery to produce the corresponding protein/antigen which, hence, induce the desired immune response. − Different virus vectors can be used to achieve this strategy − and include replication-defective adenovirus. − …”

Vaccine Development for Herpes Simplex Viruses: A Commentary of Special Issue Editors

“…In line with these results, another enthralling strategy is reviewed by Richard Voellmy and coworkers [13]. They describe HSV-1 replication-competent-controlled viruses (RCCVs) for application to skin or mucosal membranes.…”