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

Edward Jenner tested the first vaccine that was aimed at small pox in 1796. Overall, vaccination has
been a very successful approach for disease prevention. However, more than two centuries after the
first vaccine use, there still remain diseases and conditions that cannot be effectively prevented or
treated by vaccination. Unfortunately, the diseases that have remained refractory to vaccination or
that are insufficiently protected against by vaccination include diseases of global concern including
influenza/flu, tuberculosis, malaria, HIV/AIDS, and oral and genital herpes. While vaccine
development efforts based on the “classical” paradigm (described below) are continuing, it may be
appropriate to also consider novel approaches that may have a potential for inducing qualitatively
and/or quantitatively superior immune responses.
A primary limitation in developing innovative vaccines against today and tomorrow’s
challenginginfectious diseases is our inability to understand the molecular basis of current Liveattenuated
vaccines attenuation andimmunogenicity. This is mainly because of the empiric nature of
their development [1,2]. Most currently licensed vaccines are either subunit vaccines (comprising
isolated proteins or protein fractions) or attenuated forms of disease-causing microorganisms.
Attenuation of pathogens is achieved by their killing or by genetic disablement of their replicative
ability. While attenuation provides the required safety, it almost universally compromises the ability of
so-modified pathogens to induce robust inflammatory responses, which translates in suboptimal
humoral and T-cell responses [3-6]. It is obviously not feasible to compare immune responses elicited
by a wild type pathogenic agent vs. those induced by an attenuated agent. However, several studies
have compared immune responses elicited by viral vectors that were attenuated but had retained
residual replicative ability and corresponding vectors that were replication-incompetent [7-10]. Results
indicated that attenuated viruses that retained some replication ability induced more complete and
more potent immune responses than non-replicating comparison viruses.
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 [11]. Replication is understood here as propagation of the agent.
Bramson [12] endorsed that 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.