Current Pharmaceutical Design - Volume 13, Issue 19, 2007

New compounds having affinity to various melanocortin receptors have recently been identified as possible neuroprotective agents. This review is focused on the role of neuroprotective effects of melanocortins in CNS injury and repair mechanisms. Using selective non-peptidic compounds with varying affinity to melanocortin receptors, our laboratory has shown their anti-edematous effects in the spinal cord injury. This effect of the compounds is related with their ability to attenuate blood-spinal cord barrier permeability. The functional significance and possible therapeutic strategies of these compounds in CNS injury are discussed.

Alzheimer's disease (AD) is the most common age-associated neurodegenerative disease in the world. The major neuropathological features of AD are synaptic loss, neuronal loss, neurofibrillary tangles and the deposition of amyloid- β (Aβ) as plaques and in cerebral blood vessels. Numerous Aβ targeting therapeutic approaches have been shown to prevent amyloid deposition and resulting in cognitive improvement in transgenic mouse models of AD. Some of these approaches are currently in early clinical trials. It remains to be seen if these approaches will be proven effective in patients. Future anti-AD therapies will likely be multi-modal and individually tailored depending on the patient's immune status, genetic background and their amyloid burden, as determined by imaging studies using Aβ specific labeling ligands. Preclinical data suggests that it will be much more feasible to prevent AD related pathology, then to clear existing pathology, making early diagnosis critically important.

Vaccination is a potent and cost-effective counter-measure to the threat of infectious diseases. Effective vaccines have been developed against polio, measles, mumps, hepatitis B, and recently against human papliomavirus, which is associated with cervical cancer. Despite these successes, there are many challenges for vaccine design against numerous viral and bacterial disease, particularly for ermerging pathogens and potential biodefense pathogens, such as avian influenza, SARS, tularemia, anthrax, west nile, and others. In this issue of Current Pharmaceutical Design, the authors address the current status and future challenges for vaccine strategies [1-7]. References [1] McBurney SP, Ross TM. Developing Broadly Reactive HIV-1/AIDS Vaccines: A Review of Polyvalent and Centralized HIV-1 Vaccines. Curr Pharm Des 2007; 13(19): 1957-1964. [2] Ramachandran S, Kinchington PR. Potential Prophylactic and Therapeutic Vaccines for HSV Infections. Curr Pharm Des 2007; 13(19): 1965-1973. [3] Ferenczy MW. Prophylactic Vaccine Strategies and the Potential of Therapeutic Vaccines Against Herpes Simplex Virus. Curr Pharm Des 2007; 13(19): 1975-1988. [4] Kristoff J. Malaria Stage-Specific Vaccine Candidates. Curr Pharm Des 2007; 13(19): 1989-1999. [5] Poonam P. The Biology of Oral Tolerance and Issues Related to Oral Vaccine Design. Curr Pharm Des 2007; 13(19): 2001-2007. [6] Price AA. Meningococcal Vaccines. Curr Pharm Des 2007; 13(19): 2009-2014. [7] Karkhanis LU. Ross TM. Mucosal Vaccine Vectors: Replication-Competent Versus Replication-Deficient Poxviruses. Curr Pharm Des 2007; 13(19): 2015-2023.

The development of an HIV/AIDS vaccine requires consideration of the large diversity of viral isolates. In 2005, there were 5 million new cases of HIV infection and over 4 million deaths due to AIDS. An HIV vaccine is needed to prevent the spread of this virus. One of the greatest challenges to developing a preventative HIV vaccine is the diversity of HIV-1 isolates. Env sequences can differ by as much as 35% between isolates from different clades and by as much as 10% within a clade. Two main strategies to address viral diversity for HIV vaccine development are the use of polymericor centralized-based immunogens. Polymeric-based vaccines, which have been used for polio and pneumococcus vaccines, use components from a range of viral isolates to increase the breadth of immune recognition. Centralized sequences decrease the sequence diversity by encoding the most common amino acid at each position from a diverse pool of viral isolates. These sequences are derived using the consensus, center-of-the-tree, or ancestral methods. The use of polyvalentand centralized-based vaccines induce broadly reactive immune responses, however it is unclear whether the use of these sequences will increase protection against diverse HIV-1 infection. This review will summarize the current uses of polyvalent and centralized vaccines to increase immune breadth that may determine future directions for HIV-1 vaccine development.

The human herpesviruses herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) can cause severe recurrent disease in humans and establish lifelong infection in their hosts. Several antiviral therapies are available to control disease and spread, but these are not completely effective and do not affect latent virus. The need for vaccines for HSV is urgent, both for controlling initial infection and spread of disease as well as to limit recurrences. Several approaches including subunit vaccines, peptide vaccines, live virus vectors and DNA vaccine technology have been used in developing both prophylactic and therapeutic vaccines for HSV and these are reviewed here.

Herpes Simplex Virus Type 1 (HSV-1) infection is widespread and causes significant disease. A number of prophylactic vaccine strategies have elicited protective immunity in animal models, but no human vaccine has yet been effective. Asymptomatic HSV-1 infection is common, demonstrating that the immune system is able to control infection, despite failure to clear the virus. Therefore, therapeutic vaccination may be a viable strategy against HSV-1. This review will discuss the epidemiology, molecular biology, and immune response to HSV-1, prophylactic and therapeutic vaccine strategies, and the potential of future therapeutic HSV-1 vaccines to reduce or eliminate HSV-1 pathology.

Malaria causes 300-500 million clinical cases and 1-3 million deaths per year, the majority of which occur in African children less than five years of age. The failure of vector control methods to achieve adequate reductions in morbidity and mortality and the widespread resistance to conventional antimalarial drugs have made development of an effective malaria vaccine a global priority. An ideal malaria vaccine should recapitulate naturally acquired immunity in an endemic setting. However, progress toward an efficacious vaccine has been slow, due to the high polymorphism of prospective target antigens and the inability of most vaccines to elicit long-lived immunological memory in the host. This review discusses the efficacy of current pre-erythrocytic-stage, asexual blood-stage, and transmission-blocking vaccine candidates, as well as future prospects for malaria vaccine development.

Intestinal tissues are continuously exposed to tremendous amount of foreign material, either beneficial or harmful. Although strong protective immune responses are required to clear harmful pathogen infections, similar responses against food antigen can lead to harmful inflammation. Therefore, oral tolerance or unresponsiveness against dietary and commensal bacteria is also important to maintain tissue integrity by preventing harmful inflammatory responses in the intestine. While oral tolerance is an important phenomenon to protect unnecessary inflammatory responses, it presents an obstacle in the development of oral vaccines. Therefore an understanding of the gut immune system and the induction of oral tolerance is important. This review will focus on important aspects of the intestinal immune system and how immune responses in the intestine maintain homeostasis via oral tolerance. Also it will provide new insights in the development of oral vaccines.

Neisseria meningitidis is a major world-wide cause of meningitis. N. meningitidis related diseases have become more pronounced in the last decade and changes in meningococcal-associated disease have opened new opportunities for prevention and vaccine development. Although multivalent vaccines have been developed against the N. meningitidis serogroups A, C, W-135, and Y, four of the most common serogroups, the diversity of N. meningitidis has increased the number of challenges for the development of an effective vaccine against all currently identified strains. Without the development of a vaccine against serogroup B, it will be difficult to effectively prevent global meningococcal disease. This review provides a background on N. meningitidis biology and focuses on the current status of meningococcal research and vaccine development. In addition, the efficacy of the currently marketed N. meningitidis vaccines will be discussed.

The mucosal surfaces of the respiratory, gastrointestinal, and genitourinary tract are entry points for a variety of pathogens and they serve as the first line of defense against infection. To prevent transmission of mucosal pathogens, it is often necessary to target the vaccine to the mucosal surface. Viral vectors, such as poxviruses expressing gene inserts, capable of overcoming the formidable array of host defenses at the mucosal surfaces, are an attractive vaccination strategy for mucosal immunization against infectious diseases. Replication-competent vectors, such as vaccinia, are highly effective, but have a number of safety concerns that may limit their widespread use in humans. In contrast, replication-deficient vectors, such as modified vaccinia ankara (MVA), ALVAC, and NYVAC, may be safer vectors than live vectors, but these vectors may not be as effective at inducing immune responses. Co-delivery of viral vectors with genetic adjuvants (cytokines) or deletion of certain immunomodulatory genomic sequences from these viral vectors may increase vaccine efficiency and are promising strategies for a new generation of mucosal vaccines.