Herpesvirus vaccines. Development, controversies, and applications.

Eight herpesviruses have evolved to infect humans; to persist within them; and to spread efficiently to others, generally without causing disease. Their capacity to do so reflects the genetic investment these complex DNA viruses have made in deterring host immune defenses that arise against them. The complex interplay between host and virus has made it difficult to mount useful vaccine strategies to protect against the diseases that they do occasionally inflict upon us. This article summarizes the human herpesviruses, the syndromes attributed to them, and the current state of vaccine development and prospects. The neurotropic alpha-herpesviruses include herpes simplex viruses (HSV) types 1 and 2, the causes of mucocutaneous herpes infections, and varicella-zoster virus (VZV), which causes chickenpox and zoster. Cytomegalovirus (CMV), which infects lymphocytes, monocytes, and neutrophils, and the lymphotropic human herpesviruses 6 and 7 (HHV-6 and HHV-7), are classified based on their genetic content as beta-herpesviruses. The two human gamma-herpesviruses, Epstein-Barr virus (EBV) and human herpesvirus 8 (also known as Kaposi's sarcoma-associated herpesvirus ), both cause human cancers. Once a herpesvirus infects humans, it establishes a tenacious foothold, one that permits it to persist within us for life. The viruses can do so because they carry effective genetic tools to thwart the very immune mechanisms that successfully terminate other classical virus infections, such as polio, smallpox, and influenza. All herpesviruses establish latency, during which they express few if any protein antigens that could betray their presence to immune effector elements. In addition, they all possess means of down-regulating their presentation in the context of class I major histocompatibility complex (MHC) proteins. 21,61 Some examples of these two mechanisms of immune deterrence help illustrate the rich complexity of the challenge that herpesviruses manifest as vaccine targets. HSVs rapidly spread from the mucocutaneous sites at which they are initially deposited onto human tissues to nearby sensory nerve endings. The virus core particles ascend the nerves and establish residence for life in neuronal nuclei. There, they express only one family of RNAs, ones that probably do not encode any proteins, but which enhance the ability to reactivate periodically. During latency, HSVs are truly invisible to immune surveillance. CMVs illustrate a different and highly successful series of strategic approaches to immune avoidance. It encodes at least four proteins that block viral antigen presentation in the content of MHC. 58 It is so efficient at doing so that CMV-infected cells display little or no MHC proteins, stripping them, as it were, of the very labels that identify them as parts of ourselves. As such, they become susceptible to killing by natural killer cells, which are programmed to attack anything that lacks MHC proteins. CMV solves this dilemma by also encoding a protein that resembles an MHC protein, but which is not functional in antigen presentation. What capacity can a vaccine have to circumvent these formidable and highly evolved herpesvirus strategies for avoiding immune surveillance? The answer to this depends on what one hopes the vaccine to achieve. It is probably futile to presume that it could totally prevent infection, or the establishment of latency, once the infection has been initiated. But a vaccine that greatly limits the total quantity of virus that replicates at the time of initial infection may prevent significant acute illness, and there may be a smaller reservoir of latent virus from which reactivated infections might arise. Live-attenuated vaccine strains represent some of the earliest approaches to developing herpesvirus vaccines. These vaccines have the theoretical advantage of presenting all viral antigens in a natural context. The challenge is to identify a vaccine strain that is adequately immunogenic while being safe. Because of the role cell-mediated immunity (CMI) plays in containing herpesvirus reactivations, individuals with impaired CMI often are at risk for more severe infections, either with wild-type or vaccine strains. Because mild immunocompromise may be undetected in children prior to vaccination, it is important for vaccine strains to be attenuated adequately. On the other hand, many candidate herpesvirus vaccines (including some early varicella vaccines) proved to be too attenuated to induce adequate immune responses. Moreover, the issue of latency and reactivation is particularly important in live-attenuated vaccine development, because their ability to reactivate may limit the long-term safety of the vaccine. The difficulty in adjusting vaccine attenuation so that the virus is sufficiently immunogenic but not virulent for compromised patients led to several alternative strategies using noninfectious reagents. Although safe, these in turn have been bedeviled by insufficient immunogenicity. Several herpesvirus vaccine strategies are summarized in Table 1, and their current and potential roles in preventing herpesvirus diseases are reviewed next. We begin with and emphasize VZV because a vaccine is licensed for prevention of varicella.