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PubMed2006

Domains of group A streptococcal M protein that confer resistance to phagocytosis, opsonization and protection: implications for vaccine development.

Streptococcus pyogenes (group A streptococcus) colonizes skin and throat tissues resulting in a range of benign and serious human diseases. Opsonization and phagocytosis are important defence mechanisms employed by the host to destroy group A streptococci. Antisera against the cell-surface M protein, of which over 150 different types have been identified, are opsonic and contribute to disease protection. In this issue of Molecular Microbiology, Sandin and colleagues have comprehensively analysed the regions of M5 protein that contribute to phagocytosis resistance and opsonization. Human plasma proteins bound to M5 protein B- and C-repeats were shown to block opsonization, an observation that needs to be carefully considered for the development of M protein-derived vaccines. While safe and efficacious human group A streptococcal vaccines are not commercially available, candidate M protein-derived vaccines have shown promise in murine vaccine models and a recent phase 1 human clinical trial.

Animals↗
PubMed1996

Update on the issues of HIV vaccine development.

Major scientific obstacles blocking the development of a successful preventive HIV vaccine are the extraordinary variability of HIV, the lack of an exact animal model of HIV-induced AIDS, and the lack of understanding of the correlates of positive immunity to HIV. Current HIV vaccines containing the HIV gp120 envelope have been tested in phase I and II trials but they have had a major limitation of neutralizing only T-cell tropic laboratory-adapted HIV strains grown in T-cell lines, but not neutralizing HIV primary isolates. Phase III trials of monovalent HIV gp120 envelope vaccines are being planned in the US and Thailand, but concern has been raised that recombinant monovalent gp120 may not be an appropriate immunogen for an efficious HIV vaccine. Because the immune response is probably responsible for controlling the viral load in some long-term survivors of HIV infection, studies are now being carried out to induce similar immunity against a broad spectrum of strains of HIV primary isolates with targeted HIV experimental immunogens.

AIDS Vaccines↗
PubMed2000

Respiratory syncytial virus vaccine development.

Respiratory syncytial virus is the major respiratory pathogen of infants and children worldwide. Currently, there is no effective vaccine to protect against respiratory syncytial virus infection. Immunoprophylaxis with hyperimmune globulin or with a humanized monoclonal antibody is expensive, limited to children with underlying disease, and not practical for general use. Antiviral therapy is controversial and of limited effectiveness. New approaches to the development of a vaccine for respiratory syncytial virus infection are promising. Several subunit vaccines and live attenuated virus vaccines are immunogenic and safe in children and adults. This review focuses on potential vaccine candidates and the challenges these candidate vaccines must overcome.

Adult↗
PubMed2003

Vaccine development for capsulate bacteria causing pneumonia.

Pneumonia strikes the extremes of the age spectrum, causing maximal death and disability in children and the elderly. Despite its worldwide impact, there is a paucity of epidemiologic data regarding its incidence and the causative organisms. The two leading causes of bacterial pneumonia in childhood are Streptococcus pneumoniae (SP) and Haemophilus influenzae type b (Hib). SP is the major cause of pneumonia beyond the newborn period. In neonates, Group B Streptococcus (GBS) remains a major cause of sepsis and pneumonia despite recent reductions due to targeted perinatal antibiotic prophylaxis. Hib vaccine can prevent pneumonia in developing countries. SP conjugate vaccine prevents X-ray confirmed pneumonia in low incident populations, but protection appears more marginal in high incident populations. Non-vaccine SP serotypes have demonstrated increased carriage and mucosal disease, but not invasive disease following vaccination. GBS vaccines are in the early stages of clinical development as prenatal or antenatal vaccines.

Bacterial Capsules↗
PubMed2006

Advances in vaccine development against the pre-erythrocytic stage of Plasmodium falciparum malaria.

With approximately 2.4 billion people at risk, Plasmodium falciparum malaria infection caused by an infectious bite of an Anopheles mosquito continues to be a major cause of mortality and morbidity, mainly in the tropics and subtropics. Measures to control the mosquito vector on a broad scale are expensive and need to be maintained continuously. The rapid emergence of parasite strains that are resistant to affordable drugs highlights the urgent need for a cheap and effective vaccine. Candidate vaccines that have been developed to date target different stages of the parasite life cycle. This review describes the recent advances in the development of a vaccine that aims to terminate the infection at its first stage in the liver. The candidate vaccines that are currently under clinical evaluation are introduced and the results from recent trials discussed. The review aims to explain the immunologic challenges a successful vaccine has to meet, as well as the different strategies that are currently employed in an attempt to induce a protective immune response. Furthermore, an outline of available options to be tested in the near future will be presented.

Amino Acid Sequence↗
PubMed2003

[Present situation of influenza vaccine development].

Influenza is a highly contagious acute respiratory disease, caused by influenza viruses infecting the host at the respiratory mucosa and repeated annually by appearance of variant viruses with altered surface antigens. To control influenza, a protective immunity must be provided in advance by administration with an inactivated or attenuated virus vaccine. Current inactivated vaccine, licensed for parenteral administration, can induce systemic IgG antibodies, but not highly cross-reactive mucosal IgA and heterosubtypic cytotoxic T lymdhocytes(CTL), to results in lowered protective efficacy against variant virus infection. Current attenuated virus vaccine, licensed for intranasal administration, can induce IgA and CTL, as well as IgG, with coryza, sore throat and febrile reactions and with forbidden use to high-risk patients. To improve shortcomings of the current inactivated or attenuated vaccine, many trials, including the development of DNA vaccine, are still going on.

Antibodies, Viral↗
PubMed1992

Localization of Epstein-Barr virus cytotoxic T cell epitopes using recombinant vaccinia: implications for vaccine development.

There is considerable interest in designing an effective vaccine to the ubiquitous Epstein-Barr virus (EBV). An important role for EBV-specific cytotoxic T lymphocytes (CTLs) in eliminating virus-infected cells is well established. Limited studies using a small number of immune donors have defined target epitopes within the latent antigens of EBV. The present study provides an extensive analysis of the distribution of class I-restricted CTL epitopes within EBV-encoded proteins. Using recombinant vaccinia encoding individual EBV latent antigens (Epstein-Barr nuclear antigen [EBNA] 1, 2, 3A, 3B, 3C, LP, and LMP 1), we have successfully localized target epitopes recognized by CTL clones from a panel of 14 EBV-immune donors. Of the 20 CTL epitopes localized, five were defined at the peptide level. Although CTL clones specific for nine epitopes recognized both type 1 and type 2 transformants, a significant number of epitopes (7/16 epitopes for which EBV type specificity was determined) were detected only on type 1 EBV transformants. Vaccinia recombinants encoding EBNA 3A and EBNA 3C were recognized more frequently than any other vaccinia recombinants used in this study, while no CTL epitopes were localized in EBNA 1. Surprisingly, epitope specificity for a large number of EBV-specific CTL clones could not be localized, although vaccinia recombinants used in this study encoded most of the latent antigens of EBV. These results suggest that any EBV vaccine based on CTL epitopes designed to provide widespread protection will need to include not only latent antigen sequences but also other regions of the genome. The apparent inability of human CTLs to recognize EBNA 1 as a target antigen, often the only latent antigen expressed in Burkitt's lymphoma and nasopharyngeal carcinoma, suggests that EBV-specific CTL control of these tumors will not be feasible unless the down-regulation of latent antigens can be reversed.

Amino Acid Sequence↗
PubMed2003

Kunjin virus replicon vectors for human immunodeficiency virus vaccine development.

We have previously demonstrated the ability of the vaccine vectors based on replicon RNA of the Australian flavivirus Kunjin (KUN) to induce protective antiviral and anticancer CD8+ T-cell responses using murine polyepitope as a model immunogen (I. Anraku, T. J. Harvey, R. Linedale, J. Gardner, D. Harrich, A. Suhrbier, and A. A. Khromykh, J. Virol. 76:3791-3799, 2002). Here we showed that immunization of BALB/c mice with KUN replicons encoding HIV-1 Gag antigen resulted in induction of both Gag-specific antibody and protective Gag-specific CD8+ T-cell responses. Two immunizations with KUNgag replicons in the form of virus-like particles (VLPs) induced anti-Gag antibodies with titers of > or =1:10,000. Immunization with KUNgag replicons delivered as plasmid DNA, naked RNA, or VLPs induced potent Gag-specific CD8+ T-cell responses, with one immunization of KUNgag VLPs inducing 4.5-fold-more CD8+ T cells than the number induced after immunization with recombinant vaccinia virus carrying the gag gene (rVVgag). Two immunizations with KUNgag VLPs also provided significant protection against challenge with rVVgag. Importantly, KUN replicon VLP vaccinations induced long-lasting immune responses with CD8+ T cells able to secrete gamma interferon and to mediate protection 6 to 10 months after immunization. These results illustrate the potential value of the KUN replicon vectors for human immunodeficiency virus vaccine design.

AIDS Vaccines↗