|CHAUDHURI, A RAY|
Submitted to: Vaccine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/18/2008
Publication Date: 10/11/2008
Citation: Tobin, G.J., Trujillo, J.D., Bushnell, R.V., George, L., Chaudhuri, A., Long, J., Barrera, J., Pena, L., Grubman, M.J., Nara, P.L. 2008. Deceptive Imprinting and Immune Refocusing in Vaccine Design. Vaccine. 26:6189-6199.
Interpretive Summary: Many of the world’s important human and animal pathogens including HIV, influenza and foot-and-mouth disease virus (FMDV) evade the host immune response. In this review we examine ways of counteracting this weakness by genetically engineering changes in the above viruses. FMDV causes an economically devastating disease of cloven-hoofed animals. Vaccines produced by chemical inactivation of virus are available, but there are concerns about their safety and about the ability to serologically distinguish vaccinated animals from infected animals. We have previously developed a viral subunit vaccine which does not contain infectious FMDV and lacks the genetic information for a number of viral nonstructural proteins. Thus, production of this vaccine does not require expensive high-containment manufacturing facilities, can be made in the U.S., which currently prohibits work with infectious FMDV on the mainland, and animals inoculated with this marker vaccine can readily be differentiated from infected animals using diagnostic assays employing the viral nonstructural proteins not present in the vaccine. However, FMDV consists of 7 different serotypes and many additional subtypes so a vaccine against one type does not protect animals infected with a different virus type. In this review we discuss a possible method of generating an FMDV subunit vaccine as well as HIV, influenza and caprine arthritis encephalitis virus vaccines that can protect animals infected with other strains of these viruses. We have used recombinant DNA techniques to alter various amino acid residues in the protein shell of virus, and we present preliminary evidence that some of these changes result in vaccines that can induce an immune response against a broader range of virus strains.
Technical Abstract: A large number of the world’s most widespread and problematic pathogens evade host immune responses by inducing strain specific immunity to immunodominant epitopes with high mutation rates capable of altering antigenic profiles. The immune system appears to be decoyed into reacting to these immunodominant epitopes that offer little cross protection between serotypes or subtypes. For example, during HIV-1 infection, the immune system reacts strongly to the V1, V2, and/or V3 loops of the surface envelope glycoprotein but not to epitopes that afford broad protection against strain variants. Similarly, the host mounts strain-specific immunity to immunodominant epitopes of the influenza hemagglutinin (HA) protein. A large number of pathogens appear to exploit this weakness in the host immune system by focusing antigenic attention upon highly variable epitopes while avoiding surveillance towards more highly conserved receptor binding sites or other essential functional domains. Because the propensity of the immune system to react against immunodominant strain specific epitopes appears to be genetically hard-wired, the phenomenon has been termed “deceptive imprinting.” In this review, the authors describe observations related to deceptive imprinting in multiple systems and propose strategies for overcoming this phenomenon in the design of vaccines capable of inducing protection against highly variable pathogens.