Co-administration of plasmid-encoded granulocyte-macrophage colony-stimulating factor increases human immunodeficiency virus-1 DNA vaccine-induced polyfunctional CD4+ T-cell responses

T-cell based vaccines against human immunodeficiency virus (HIV) generate specific responses that may limit both transmission and disease progression by controlling viral load. Broad, polyfunctional, and cytotoxic CD4+T-cell responses have been associated with control of simian immunodeficiency virus/HIV-1 replication, supporting the inclusion of CD4+ T-cell epitopes in vaccine formulations. Plasmid-encoded granulocyte-macrophage colony-stimulating factor (pGM-CSF) co-administration has been shown to induce potent CD4+ T-cell responses and to promote accelerated priming and increased migration of antigen-specific CD4+ T-cells. However, no study has shown whether co-immunisation with pGM-CSF enhances the number of vaccine-induced polyfunctional CD4+ T-cells. Our group has previously developed a DNA vaccine encoding conserved, multiple human leukocyte antigen (HLA)-DR binding HIV-1 subtype B peptides, which elicited broad, polyfunctional and long-lived CD4+ T-cell responses. Here, we show that pGM-CSF co-immunisation improved both magnitude and quality of vaccine-induced T-cell responses, particularly by increasing proliferating CD4+ T-cells that produce simultaneously interferon-γ, tumour necrosis factor-α and interleukin-2. Thus, we believe that the use of pGM-CSF may be helpful for vaccine strategies focused on the activation of anti-HIV CD4+ T-cell immunity.

Safety & immunogenicity of tgAAC09, a recombinant adeno-associated virus type 2 HIV-1 subtype C vaccine in India.

Background & objective: A phase 1 trial of adeno-associated virus based HIV-1 subtype C vaccine (tgAAC09) was conducted at two sites in Germany and Belgium and one site in India. This paper reports the safety and immunogenicity of tgAAC09 in healthy adult Indian volunteers. Methods: Between January 2005 and December 2006, 30 consenting volunteers were enrolled in the placebo controlled double-blind dose-escalation trial [3x109, 3x1010 and 3x1011 DNase resistant particles (DRPs)/ml]. Single injection of the candidate vaccine was administered to ten volunteers randomized in 8:2 ratio in vaccine and placebo arms at each dosage level. Results: The mean age of study volunteers (16 men and 14 women) was 34 yr. Six local reactogenicity events and 14 systemic reactogenicity events like malaise, fever, headache and myalgia were reported, both were dose-dependent. The difference between the adverse events reported by vaccine and placebo recipients (79 and 67%) was not significant. A modest IFN-γ ELISPOT response [248 spot forming units (SFU)/million cells] was detected in one volunteer from high dose group and low response (56 and 75 SFU/million cells) in two volunteers in low and mid-dose groups. A post-vaccination dose-dependent increase was observed in anti AAV2 neutralizing titres. None of the volunteers showed a positive antibody response to HIV-1. Interpretation & conclusions: The trial was a benchmark in phase I clinical evaluation of HIV candidate vaccines in India. The vaccine was generally well tolerated and raised no safety concerns. The vaccine was found to be weakly immunogenic. It is essential to understand the role of pre-existing immunity against vectors and significance of evaluation in a prime-boost strategy.

Is an HIV vaccine possible?

The road to the discovery of a vaccine for HIV has been arduous and will continue to be difficult over the ensuing twenty years. Most vaccines are developed by inducing neutralizing antibodies against the target pathogen or by using attenuated strains of the particular pathogen to engender a variety of protective immune responses. Unfortunately, simple methods of generating anti-HIV antibodies have already failed in a phase III clinical trial. While attenuated SIV variants work well against homologous challenges in non-human primates, the potential for reversion to a more pathogenic virus and recombination with challenge viruses will preclude the use of attenuated HIV in the field. It has been exceedingly frustrating to vaccinate for HIV-specific neutralizing antibodies given the enormous diversity of the Envelope (Env) glycoprotein and its well-developed glycan shield. However, there are several antibodies that will neutralize many different strains of HIV and inducing these types of antibodies in vaccinees remains the goal of a vigorous effort to develop a vaccine for HIV based on neutralizing antibodies. Given the difficulty in generating broadly reactive neutralizing antibodies, the HIV vaccine field has turned its attention to inducing T cell responses against the virus using a variety of vectors. Unfortunately, the results from Merck's phase IIb STEP trial proved to be disappointing. Vaccinees received Adenovirus type 5 (Ad5) expressing Gag, Pol, and Nef of HIV. This vaccine regimen failed to either prevent infection or reduce the level of HIV replication after challenge. These results mirrored those in non-human primate testing of Ad5 using rigorous SIV challenge models. This review will focus on recent developments in HIV vaccine development. We will deal largely with attempts to develop a T cell-based vaccine using the non-human primate SIV challenge model.

The hope for an HIV vaccine based on induction of CD8+ T lymphocytes: a review

The only long-term and cost-effective solution to the human immunodeficiency virus (HIV) epidemic in the developing world is a vaccine that prevents individuals from becoming infected or, once infected, from passing the virus on to others. There is currently little hope for an AIDS vaccine. Conventional attempts to induce protective antibody and CD8+ lymphocyte responses against HIV and simian immunodeficiency virus (SIV) have failed. The enormous diversity of the virus has only recently been appreciated by vaccinologists, and our assays to determine CD8+ lymphocyte antiviral efficacy are inadequate. The central hypothesis of a CTL-based vaccine is that particularly effective CD8+ lymphocytes directed against at least five epitopes that are derived from regions under functional and structural constraints will control replication of pathogenic SIV. This would be somewhat analogous to control of virus replication by triple drug therapy or neutralizing antibodies.

A pilot study on willingness to participate in future preventive HIV vaccine trials.

BACKGROUND & OBJECTIVES: In India, phase-I human clinical trials for a preventive HIV vaccine are being conducted at Pune and Chennai Centres. In order to find out the willingness of populations at risk to participate in future preventive HIV vaccine trials (HIVVTs) and to assess the factors that enhance or deter them from participation, a study was conducted at Chennai and Madurai in Tamil Nadu. METHODS: This cross-sectional study was conducted among transport workers, people attending sexually transmitted infection clinics, injection drug users, men having sex with men, women in sex industry and a representative sample of monogamous married women, by employing measurement scales. A structured questionnaire on knowledge and attitudes about the HIV vaccine was used to measure the participants' knowledge and attitudes about HIV vaccine and HIVVTs. RESULTS: Of the 112 participants, 67 (60%) were men. Mean age of the respondents was 32 yr; 68 per cent were high school educated. Majority of respondents were willing to participate in a future HIVVT and the reasons were altruism, protection from HIV, and support for the researchers. Major concerns were vaccine efficacy, side effects of the vaccine and the impact of a HIV vaccine on the participants' lives. Majority (85%) agreed that sex without condom would not be safe despite the availability of an HIV vaccine. INTERPRETATION & CONCLUSION: It is likely that high-risk volunteers will be willing to enroll in HIVVTs. Barriers and concerns should be dealt with carefully by providing correct information. Also there is a need for more education to ensure participants' understanding of key concepts of HIV vaccine trial.

Vacinas em desenvolvimento: estreptococo do grupo B, herpes-zóster, HIV, malária e dengue / Vaccines under development: group B streptococcus, herpes-zoster, HIV, malaria and dengue

OBJETIVOS: As vacinas contra o estreptococo B, o herpes-zóster, o HIV, a malária e a dengue, selecionadas por critérios de comercialização iminente ou devido a problemas específicos para sua obtenção, foram objeto de uma revisão sobre o estado atual do seu desenvolvimento. FONTE DOS DADOS:Foi realizada revisão da literatura através da MEDLINE no período de 1996 a 2006, sobre a epidemiologia e imunologia das doenças, analisando tanto os maiores problemas para a obtenção de uma vacina como o estado atual dos estudos, com ênfase para os que estavam em fase mais adiantada. SíNTESE DOS DADOS: Cada uma das cinco doenças escolhidas apresenta problemas específicos para o desenvolvimento de uma vacina. No entanto, a maioria deles já foi ou está em vias de ser resolvido, permitindo prever que uma vacina - ou vacinas - eficaz e segura estará disponível em futuro próximo. CONCLUSÕES:Apesar dos problemas enfrentados para o desenvolvimento dessas vacinas, os avanços da biologia molecular e da imunologia permitiram superar a maioria deles, abrindo a perspectiva para a obtenção de novas vacinas.

AIDS vaccine: present status and future challenges.

Development of a preventive vaccine for HIV is the best hope of controlling the AIDS pandemic. HIV has, however, proved a difficult pathogen to vaccinate against because of its very high mutation rate and capability to escape immune responses. Neutralizing antibodies that can neutralize diverse field strains have so far proved difficult to induce. Adjuvanting these vaccines with cytokine plasmids and a "prime-boost," approach is being evaluated in an effort to induce both CTL and antibody responses and thereby have immune responses active against both infected cells and free viral particles, thereby necessitating fewer doses of recombinant protein to reach maximum antibodies titers. Although obstacles exist in evaluation of candidate HIV vaccines, evidence from natural history studies, new molecular tools in virology and immunology, new adjuvants, new gene expression systems, new antigen delivery systems, recent discoveries in HIV entry and pathogenesis, and promising studies of candidate vaccines in animal models have provided reasons to hope that developing a safe and effective AIDS vaccine is possible and within reach.

Construction and immunogenicity study of a 297-bp humanized HIV V3 DNA of an approximated last common ancestor in mice.

DNA immunization represents one of the promising HIV-1 vaccine approaches. To overcome the obstacle of genetic variation, we used the last common ancestor (LCA) or "center-of-the-tree" approach to study a DNA fragment of the HIV-1 envelope surrounding the V3 region. A humanized codon of the 297-bp consensus ancestral sequence of the HIV-1 envelope (codons 291-391) was derived from the 80 most recent HIV-1 isolates from the 8 circulating HIV-1 subtypes worldwide. This 297-bp humanized "multi-clade" V3 DNA was amplified by a PCR-based technique. The PCR product was well expressed in vitro whereas the corresponding non-humanized V3 DNA (subtype A/E) could not be expressed. However, both V3 DNA constructs as well as the full-length HIV-1 envelope construct (A/E) were found to be immunogenic in mice by the footpad-swelling assay. Moreover, intracellular and extracellular interferon-gamma could be detected upon in vitro stimulation of spleen cells although the response was relatively weak. Further improvement of our humanized V3 DNA is needed.