HIV-1 prophylactic vaccine trials in Thailand

The HIV epidemic has resulted in medical, social and economic consequences. There is general agreement that a safe, effective and affordable preventive HIV vaccine is urgently needed to control the epidemic. To date, over 60 phase I/II trials of about 30 candidate vaccines have been conducted worldwide. In 1991, Thailand was selected by WHO, UNAIDS as one of the countries for potential HIV vaccine evaluation sites, and 10 projects with HIV phase I, II and III trials have been conducted since 1994. Strong national commitment, collaboration both at national and international levels together with infrastructure strengthening and capacity building, are very important for success. The vaccine designs pursued included synthetic peptides, recombinant protein and recombinant viral vectors followed by or with boosting doses of recombinant proteins. All phase I/II trials indicated that the candidate vaccines were safe and produced binding and a certain level of neutralizing antibodies. The recombinant vector vaccines produced both humoral and cell-mediated responses. The AIDSVAX phase III trial conducted in 1999 was the first efficacy trial of HIV vaccine in Thailand that brought valuable information for further HIV vaccine development. Recently, a phase III trial of ALVAC-HIV priming with AIDSVAX B/E boosting was launched in 2003, and the findings of this trial will be shared with the international community. With committed parties in medical science, government, industry and the community, we hope that we can achieve success in developing a safe and effective HIV vaccine in the near future.     

AIDS疫苗研究进展

AIDS疫苗研究过程充满了坎坷和挫折。第一代基于gp120蛋白抗原的AIDS疫苗在欧美和泰国的Ⅲ期临床试验先后失败;代表第二代疫苗设计的Merck公司的腺病毒载体T细胞疫苗不但未提供保护性免疫,反而在特定人群中增加了感染几率。但科学家们仍不断推出新的疫苗设计思路,如免疫原筛选策略和基于结构生物学的免疫原设计策略等。当AIDS疫苗研究走完第25个年头的时候,在泰国开展的AIDSVAXB／E初始-ALvAC-HIV加强免疫的Ⅲ期临床试验中终于观察到了部分的保护效果,这一结果重新点燃了人们对AIDS疫苗研制成功的信心。     

Funding support lacking in search for HIV vaccine

AIDSVAX is the only vaccine in phase III efficacy trials, but most experts do not believe that this vaccine is the final word in HIV prevention. Another phase III trial could be at least 3 years away, because no other vaccines are near that stage of development. HIV-1 Delta 4 is a vaccine in development that uses a mutated form of the virus; however, there are public health concerns about introducing a new form of the virus into the population. Canary pox-vector vaccine is discussed and five versions of the vaccine are in early clinical trials. Two DNA vaccines are also being investigated.     

Controversial HIV vaccine enters phase III trials amid skepticism

Clinics have begun enrolling volunteers in the first phase III trial of an HIV vaccine. Developing the vaccine has been a goal for nearly two decades, but leading scientists are skeptical about the effectiveness of a vaccine which does not use live viruses. More than 34 different candidate vaccines have been tested in phase I, and three are in phase II. The vaccine, AIDSVAX, is designed to train the immune system to protect itself against infection by creating antibodies. The scientific and political issues associated with the vaccine are presented.     

First AIDS vaccine tested did not protect,but gives scientific leads

AIDSVAX, the first HIV preventive vaccine to finish a human efficacy trial, did not protect against infection, but is likely to provide much information on designing better vaccines.     

Combining drug and immune therapy: a potential solution to drug resistance and challenges of HIV vaccines?

According to the World Health Organization's 2007 estimates, close to 33 million people worldwide are living with HIV/AIDS. Over the past two decades, significant progress has been made in understanding HIV pathogenesis and disease progression, which has allowed the identification of a multitude of drug and vaccine targets. Although currently available drug therapies have greatly increased the time from HIV infection to development of AIDS, drug resistance is an inevitable consequence that limits the duration of successful treatment. Consequently, a preventative vaccine remains the top priority; however, no vaccine trial performed to date has shown efficacy in human trials. Therefore, we must use all of our current resources in new creative therapies and strive to develop new methods to reduce persistent viral levels until an effective preventative vaccine is developed. One possible strategy is to use therapeutic vaccination or immune modulators to augment the immune response while antiretroviral chemotherapy limits viral replication. This combination approach is being utilized with success in the treatment of Hepatitis B infections and several trials have been completed and others are ongoing to determine the potential of combination immunological and chemical therapies for HIV infection. We will review the progress to date of anti-HIV drugs, preventative vaccines, and therapeutic vaccines and discuss the future strategies of combination drug and vaccine therapeutic strategies in the fight against HIV.     

Factors associated with incarceration and incident human immunodeficiency virus (HIV) infection among injection drug users participating in an HIV vaccine trial in Bangkok, Thailand, 1999–2003

Aims To determine if incarceration was associated with human immunodeficiency virus (HIV) infection and identify risk factors for incarceration among injection drug users (IDUs) participating in an HIV vaccine trial in Bangkok. Design The AIDSVAX B/E HIV vaccine trial was a randomized, double‐blind, placebo‐controlled study. A proportional hazards model was used to evaluate demographic characteristics, risk behavior and incarceration as predictors of HIV infection and generalized estimation equation logistic regression analysis to investigate demographic characteristics and risk behaviors for predictors of incarceration. Setting The trial was conducted in Bangkok Metropolitan Administration drug‐treatment clinics, 1999–2003. Participants A total of 2546 HIV‐uninfected IDUs enrolled in the trial. Measurements HIV testing was performed and an interviewer‐administered questionnaire was used to assess risk behavior and incarceration at baseline and every 6 months for a total of 36 months. Findings HIV incidence was 3.4 per 100 person‐years [95% confidence interval (CI), 3.0–3.9] and did not differ among vaccine and placebo recipients. In multivariable analysis, being in jail (P < 0.04), injecting (P < 0.0001), injecting daily (P < 0.0001) and sharing needles (P = 0.02) were associated with HIV infection and methadone maintenance was protective (P = 0.0006). Predictors of incarceration in multivariable analysis included: male sex (P = 0.04), younger age (P < 0.0001), less education (P = 0.001) and being in jail (P < 0.0001) or prison (P < 0.0001) before enrollment. Conclusions Among IDUs in the AIDSVAX B/E trial, incarceration in jail was associated with incident HIV infection. IDUs in Thailand remain at high risk of HIV infection and additional prevention tools are needed urgently. HIV prevention services, including methadone, should be made available to IDUs.     

NIH conference. Development and evaluation of a vaccine for human immunodeficiency virus (HIV) infection

The development of a safe and effective vaccine for infection with human immunodeficiency virus (HIV) is complicated by several unique scientific, logistic, and ethical issues. These issues include a lack of understanding of protective immunity to HIV and disease development, the absence of an adequate and convenient animal model for studying HIV infection, and difficulties in phase III evaluation of candidate vaccines. Because HIV can be transmitted as either a cell-free or cell-associated virus, a protective immune response against HIV infection will likely require both humoral and cell-mediated immunity. A neutralizing antibody against HIV and an antibody involved in antibody-dependent cellular cytotoxicity have been shown in HIV-infected persons, but their precise relation to protection is unclear. Cytotoxic lymphocytes from HIV-infected persons have been shown to lyse target cells expressing HIV or its proteins. Cloned T cells have been developed that manifest HIV-specific, major histocompatibility-complex class I-restricted cytotoxic capabilities that are broadly specific. Thus far, all attempts to protect chimpanzees, currently the only suitable animal model, from HIV infection have failed. Ongoing vaccine studies in humans include phase I trials of recombinant proteins of the HIV envelope in uninfected persons as well as the administration of whole killed virus to persons already infected with HIV. Rapid progress is being made in the development of new animal models for HIV infection. The establishment of alternative animal models, both primate and small animal models, will greatly facilitate the development of a vaccine for HIV infection.     

Major vaccine trials begin

March 8 marked the beginning of the first HIV vaccine effectiveness trial in the San Francisco Bay Area, being conducted by the San Francisco Department of Public Health and the University of California at San Francisco. This phase III trial is expected to run four years in more than 50 locations, and enroll 5,000 participants in the U.S. The study will test a recombinant vaccine known as AIDSVAX B/B, developed by VaxGen. A similar trial will enroll 2,500 injection drug users in Thailand. In related news, the National Institute of Allergy and Infectious Diseases launched a vaccine trial in Africa in February. The phase I trial will enroll 40 HIV-negative participants in Uganda and will test Alvac, a vaccine produced by Pasteur Merieux Connaught. Contact information for the San Francisco Bay Area trial is provided.     

Challenges in Mucosal HIV Vaccine Development: Lessons from Non-Human Primate Models

An efficacious HIV vaccine is urgently needed to curb the AIDS pandemic. The modest protection elicited in the phase III clinical vaccine trial in Thailand provided hope that this goal might be achieved. However, new approaches are necessary for further advances. As HIV is transmitted primarily across mucosal surfaces, development of immunity at these sites is critical, but few clinical vaccine trials have targeted these sites or assessed vaccine-elicited mucosal immune responses. Pre-clinical studies in non-human primate models have facilitated progress in mucosal vaccine development by evaluating candidate vaccine approaches, developing methodologies for collecting and assessing mucosal samples, and providing clues to immune correlates of protective immunity for further investigation. In this review we have focused on non-human primate studies which have provided important information for future design of vaccine strategies, targeting of mucosal inductive sites, and assessment of mucosal immunity. Knowledge gained in these studies will inform mucosal vaccine design and evaluation in human clinical trials.     

What is new in HIV/AIDS research in developing countries?

HIV epidemic has had greatest impact in sub‐Saharan Africa (SSA) and mainly in East and Southern Africa with HIV prevalence in some parts going up to 30%. In the recent years, considerable HIV research on prevention, treatment and care, and vaccine has been conducted in many developing countries and provided evidence‐based knowledge to control the epidemic. However, there have also been disappointing results in HIV prevention trials such as in HIV vaccine and microbicide trials. Despite these outcomes, important lessons have been learnt that help in designing future trials. This article examines the recent advances in HIV research in developing countries. The most recent HIV prevention research has demonstrated the effect of male circumcision on HIV acquisition, and lack of impact of HSV‐2 treatment on HIV transmission and acquisition. Use of HIV antiretroviral drugs (ARVs) for HIV prevention is a new area that has attracted interest and a number of trials are examining the effect of oral Pre‐Exposure Prophylaxis on HIV acquisition and also looking at the potential of ARVs in reducing infectiousness. Progress has been made in HIV treatment, monitoring treatment efficacy and toxicity as well as evaluation of different models of ART delivery. HIV vaccine research has, however, faced most challenges despite many efforts that have been put in. Looking into the future, there are ongoing trials that will hopefully generate important information to strengthen HIV policies in the next few years. There are, however, many other gaps in HIV research that need to be urgently addressed.     

Human immunodeficiency virus antibodies and the vaccine problem

Despite the great advances made in controlling human immunodeficiency virus type 1 (HIV‐1) infection with antiretroviral drug treatment, a safe and efficacious HIV vaccine has yet to be developed. Here, we discuss why clinical trials and vaccine development for HIV have so far been disappointing, with an emphasis on the lack of protective antibodies. We review approaches for developing appropriate HIV immunogens and the stimulation of long‐lasting B‐cell responses with antibody maturation. We conclude that candidate reagents in the pipeline for HIV vaccine development are unlikely to be particularly effective. Although the major funders of HIV vaccine research and development are placing increasing emphasis on clinical product development, a genuine breakthrough in preventing HIV infection through vaccines is more likely to come from novel immunogen research.     

Challenges for HIV vaccine dissemination and clinical trial recruitment: if we build it, will they come?

HIV vaccine availability does not guarantee uptake. Given suboptimal uptake of highly efficacious and already accessible vaccines in the United States, low vaccine coverage in the developing world, and the expectation that initial HIV vaccines will be only partially efficacious, the public health community will face formidable challenges in disseminating U.S. Food and Drug Administration (FDA)-approved HIV vaccines. HIV/AIDS stigma, fear of vaccine- induced HIV infection, social side effects of testing HIV-positive, and mistrust of government and research present additional obstacles to HIV vaccine dissemination. Increased risk behaviors because of HIV vaccine availability can undermine the effectiveness of partially efficacious vaccines in reducing HIV incidence. HIV vaccine efficacy trials also face significant challenges in recruitment of sufficient volunteers and possible increases in risk behaviors due to trial participation. Planning and designing interventions to facilitate successful recruitment for large-scale phase 3 efficacy trials is a vital step towards U.S. FDA-approved HIV vaccines. Rather than despair in the face of momentous HIV vaccine dissemination challenges, or presume unrealistically that vaccine uptake will ensue automatically and that risk behavior increases will not occur, let us deem the estimated 10-year window to an approved HIV vaccine as an opportunity to investigate and confront these challenges. A consumer research agenda founded on social marketing principles is needed to facilitate the design of empirically-based interventions tailored to the unique needs and preferences of specific segments of consumers. Social marketing interventions may increase future HIV vaccine uptake and clinical trial participation, and mitigate increases in HIV risk behaviors.     

Future access to HIV vaccines. Report from a WHO-UNAIDS Consultation, Geneva, 2-3 October 2000

Results from the first phase III efficacy trial of an HIV vaccine will be available within the next 2-3 years. Thus, it is imperative to start planning now to address how any effective vaccines should be used. In the absence of definitive information on the characteristics of the first generation of HIV vaccines, the following assumptions were made: the vaccine will (i) have only low to moderate efficacy (on the order of 50%); (ii) not be inexpensive (on the order of 10 to 30 US $ per dose); (iii) require multiple doses; and, (iv) at least initially, be available in limited quantities. A vaccine with that profile would not be suitable for general use in all countries, and it might have to be initially targeted to populations at higher risk of HIV infection. These populations will differ from region to region, according to the epidemiological situation. In most high and middle income countries potential target groups for an initial HIV immunization programme would include intravenous drug users, gay men, commercial sex workers, and high-risk heterosexuals, as well as healthcare workers exposed to blood. In sub-Saharan Africa, future HIV immunization programmes might include larger segments of the population. In order to plan future vaccination programmes it is important to estimate the need (size of target population) and the demand (uptake in target populations) for future HIV vaccines. In addition to the public sector demand for an HIV vaccine (to be used in public health programmes), there will also be a private sector demand driven by the willingness and ability of individuals and employers to pay for the vaccine. HIV vaccines would need to be delivered as part of comprehensive HIV prevention packages, including behavioral and health promotion interventions. This would be especially important with vaccines of moderate efficacy, in order to prevent increased risk behavior among vaccine recipients. To avoid false expectations, the vaccine message would need to be recast as part of the total prevention strategy, rather than the "magic bullet" that people have come to expect. Initial deployment of HIV vaccines could proceed through targeted vaccination campaigns, drawing from experience with other vaccines. These campaigns would be complex and expensive, and would require full participation and collaboration from all levels of the community, as well as considerable strengthening of the infrastructures required for vaccine delivery. Current candidate vaccines in phase III trials may not be appropriate for much of Africa and South Asia, two areas most in need of an HIV vaccine. Credible international efforts ('push and pull" mechanisms) are needed to create incentives for the industry to develop vaccines for these regions. Feasible financing mechanisms may have to be established to cover the cost of production and delivery of vaccines, in order to ensure equitable access to HIV vaccines around the world. In parallel to the deployment of the initial vaccine, additional bridging studies and effectiveness trials may be needed to expand vaccine use. Research should also continue at an increased pace to develop new generations of more effective vaccines, especially vaccines appropriate to Africa. Achieving these goals will require real political commitment from government and international organizations, to be materialized in specific actions and budget allocations. The daunting challenge of making future effective vaccines accessible to all populations in need will require a sustained collaborative effort on the part of all parties involved.     

Demographic factors that influence the neutralizing antibody response in recipients of recombinant HIV-1 gp120 vaccines

We compared neutralizing antibody responses in human immunodeficiency virus (HIV) type 1 gp120 vaccine recipients by age, sex, and race. Four phase 1 or 2 trials involving 505 vaccinated subjects were analyzed. Age and sex had no detectable effect on neutralizing antibody responses. However, race influenced the response to one vaccine, MN gp120, in alum. Four inoculations with this vaccine generated higher serum titers of neutralizing antibodies in African Americans than in whites. Despite potent neutralization of T cell line-adapted HIV-1, serum from these African Americans failed to neutralize primary HIV-1 isolates. Neutralizing antibody responses did not differ between races when SF2 gp120 in MF-59 was administered either alone or with recombinant canarypox vCP205; they also did not differ when vCP1452 was administered either alone or with AIDSVAX B/B in alum. These data indicate that race may affect the neutralizing antibody response to some gp120 immunogens. To fully evaluate immunogenicity, clinical trials of candidate vaccines should enroll diverse populations of subjects.     

Safety and immunogenicity of an HIV subtype B and E prime-boost vaccine combination in HIV-negative Thai adults

ALVAC-HIV (vCP1521) and AIDSVAX B/E were evaluated in a phase 1/2 trial of human immunodeficiency virus (HIV)-negative Thai adults. Of 133 volunteers enrolled, 122 completed the trial. There were no serious vaccine-related adverse events, nor were there intercurrent HIV infections. Lymphoproliferative responses to glycoprotein 120 E were induced in 63% of the volunteers, and HIV-specific CD8 cytotoxic T lymphocyte responses were induced in 24%. Antibody responses increased in frequency and magnitude in association with the dose level of AIDSVAX B/E. Binding and neutralizing antibodies to the MN strain were induced in 100% and 98%, respectively, of the volunteers receiving 600 microg of AIDSVAX B/E, and such antibodies to E strains were induced in 96% and 71%, respectively, of these volunteers. This vaccine combination was well tolerated and was immunogenic, meeting milestones for advancement to phase 3 evaluation.     

HIV/AIDS treatment and HIV vaccines for Africa

Increased support from the global HIV/AIDS community is driving advances in HIV treatment and vaccine development in the developing world. Care of patients with AIDS includes many biomedical, nutritional, psychosocial, and behavioural interventions. In resource-poor settings, antiretroviral drugs should be given with use of standardised treatment regimens and streamlined algorithms for monitoring use. A safe and effective HIV vaccine will supplement prevention efforts to protect uninfected people against infection, or might possibly be able to modify the course of HIV infection. Advances have been made in understanding the immune response and immunisation to HIV, and new ideas for candidate vaccines have been developed, including several based on HIV-1 strains prevalent in Africa. HIV vaccine efficacy trials are needed in Africa to determine whether these advances can be translated into clinical and public health benefits. In this review, we discuss the prospects for use of treatment and vaccines in resource-poor settings.     

Local understanding of an HIV vaccine and its relationship with HIV-related stigma in the Dominican Republic

The purpose of this study was to explore local perceptions and experiences regarding vaccines in general and HIV vaccines and vaccine trials in the Dominican Republic. In-depth interviews were carried out with 25 participants representing two study groups: (1) individuals considered at high risk for HIV infection including female sex workers and male STI clinic attendees and (2) individuals considered at low risk of HIV infection including women and men recruited at a general outpatient clinic. Across the groups, participants often characterized vaccines in general as having both preventive and curative properties. In turn, one of the most salient concerns regarding the receipt of an HIV vaccine was the fear that one would be labelled 'HIV positive' and stigmatized, as the vaccine may be perceived as a cure for those already infected. These findings suggest the importance of individual and community level education to clarify the nature and mechanisms of the given HIV vaccine being tested. Social support and counselling services should also accompany HIV vaccine trials and distribution plans to assist individuals in determining if and how they communicate their participation and/or receipt of an HIV vaccine to others and manage potential negative social reactions.