Showing papers on "Vaccine trial published in 2008"

The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development?

Abstract: The world of human immunodeficiency virus (HIV) vaccines has suffered a baffling setback. The first trial of a vaccine designed to elicit strong cellular immunity has shown no protection against infection. More alarmingly, the vaccine appeared to increase the rate of HIV infection in individuals with prior immunity against the adenovirus vector used in the vaccine. A new study in this issue suggests that a different vaccine approach—using a DNA prime/poxvirus boost strategy—induces polyfunctional immune responses to an HIV immunogen. The disappointing results of the recent vaccine trial suggest that a more thorough assessment of vaccine-induced immune responses is urgently needed, and that more emphasis should be placed on primate models before efficacy trials are undertaken.

Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients.

Abstract: Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-gamma responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans.

Reference Intervals in Healthy Adult Ugandan Blood Donors and Their Impact on Conducting International Vaccine Trials

Abstract: Background: Clinical trials are increasingly being conducted internationally. In order to ensure enrollment of healthy participants and proper safety evaluation of vaccine candidates, established reference intervals for clinical tests are required in the target population. Methodology/Principal Findings: We report a reference range study conducted in Ugandan adult blood bank donors establishing reference intervals for hematology and clinical chemistry parameters. Several differences were observed when compared to previously established values from the United States, most notably in neutrophils and eosinophils. Conclusions/Significance: In a recently conducted vaccine trial in Uganda, 31 percent (n=69) of volunteers screened (n=223) were excluded due to hematologic abnormalities. If local reference ranges had been employed, 83% of those screened out due to these abnormalities could have been included in the study, drastically reducing workload and cost associated with the screening process. In addition, toxicity tables used in vaccine and drug trial safety evaluations may need adjustment as some clinical reference ranges determined in this study overlap with grade 1 and grade 2 adverse events.

Evaluating a surrogate endpoint at three levels, with application to vaccine development

Abstract: Identification of an immune response to vaccination that reliably predicts protection from clinically significant infection, i.e. an immunological surrogate endpoint, is a primary goal of vaccine research. Using this problem of evaluating an immunological surrogate as an illustration, we describe a hierarchy of three criteria for a valid surrogate endpoint and statistical analysis frameworks for evaluating them. Based on a placebo-controlled vaccine efficacy trial, the first level entails assessing the correlation of an immune response with a study endpoint in the study groups, and the second level entails evaluating an immune response as a surrogate for the study endpoint that can be used for predicting vaccine efficacy for a setting similar to that of the vaccine trial. We show that baseline covariates, innovative study design, and a potential outcomes formulation can be helpful for this assessment. The third level entails validation of a surrogate endpoint via meta-analysis, where the goal is to evaluate how well the immune response can be used to predict vaccine efficacy for new settings (building bridges). A simulated vaccine trial and two example vaccine trials are presented, one supporting that certain anti-influenza antibody levels are an excellent surrogate for influenza illness and another supporting that certain anti-HIV antibody levels are not useful as a surrogate for HIV infection.

Reengineering dendritic cell-based anti-cancer vaccines.

Abstract: Despite initial enthusiasm, dendritic cell (DC)-based anti-cancer vaccines have yet to live up to their promise as one of the best hopes for generating effective anti-tumor immunity. One of the principal reasons for the generally disappointing results achieved thus far could be that the full potential of DCs has not been effectively exploited. Here, we argue that dramatic improvements in vaccine efficacy will probably require a careful re-evaluation of current vaccine design. The formulation of new strategies must take into account the natural history of DCs, particularly their role in helping the immune system deal with infection. Equally critical is the emerging importance of soluble factors, notably interleukin-12, in modulating the quality of immune responses. Vaccines should also be designed to recruit helper T cells and antibody-producing B cells rather than simply cytotoxic T lymphocytes. Finally, the judicious selection of tumor, target antigen, and disease stage best suited for treatment should serve as the foundation of trial designs. Our discussion addresses a recent clinical vaccine trial to treat early breast cancer, where many elements of this new strategy were put into practice.

Gag-Specific Cytotoxic T-Lymphocyte-Based Control of Primary Simian Immunodeficiency Virus Replication in a Vaccine Trial

Abstract: Gag-specific cytotoxic T lymphocytes (CTLs) exert strong suppressive pressure on human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. However, it has remained unclear whether they can actually contain primary viral replication. Recent trials of prophylactic vaccines inducing virus-specific T-cell responses have indicated their potential to confer resistance against primary SIV replication in rhesus macaques, while the immunological determinant for this vaccine-based viral control has not been elucidated thus far. Here we present evidence implicating Gag-specific CTLs as responsible for the vaccine-based primary SIV control. Prophylactic vaccination using a Gag-expressing Sendai virus vector resulted in containment of SIVmac239 challenge in all rhesus macaques possessing the major histocompatibility complex (MHC) haplotype 90-120-Ia. In contrast, 90-120-Ia-positive vaccinees failed to contain SIVs carrying multiple gag CTL escape mutations that had been selected, at the cost of viral fitness, in SIVmac239-infected 90-120-Ia-positive macaques. These results show that Gag-specific CTL responses do play a crucial role in the control of wild-type SIVmac239 replication in vaccinees. This study implies the possibility of Gag-specific CTL-based primary HIV containment by prophylactic vaccination, although it also suggests that CTL-based AIDS vaccine efficacy may be abrogated in viral transmission between MHC-matched individuals.

Web-based design and evaluation of T-cell vaccine candidates

Abstract: Summary: We present a suite of on-line tools to design candidate vaccine proteins, and to assess antigen potential, using coverage of k-mers (as proxies for potential T-cell epitopes) as a metric. The vaccine design tool uses the recently published ‘mosaic’ method to generate protein sequences optimized for coverage of high-frequency k-mers; the coverage-assessment tools facilitate coverage comparisons for any potential antigens. To demonstrate these tools, we designed mosaic protein sets for B-clade HIV-1 Gag, Pol and Nef, and compared them to antigens used in a recent human vaccine trial. Availability: http://hiv.lanl.gov/content/sequence/MOSAIC/ Contact: [email protected] Supplementary information: Supplementary data are available at ftp://ftp-t10.lanl.gov/pub/btk/WebToolsData

A two-dose regimen of a vaccine against Escherichia coli O157:H7 type III secreted proteins reduced environmental transmission of the agent in a large-scale commercial beef feedlot clinical trial.

Abstract: A clinical vaccine trial of commercially fed cattle tested the effect of a two-dose regimen of a vaccine product against type III secreted proteins of enterohemorrhagic Escherichia coli O157:H7 on the probability of detecting the organism on environmental sampling devices. Within commercial feedlots, pens of vaccinated and unvaccinated cattle were matched by reprocessing schedule and time of sampling. Vaccine was administered to all cattle within treated pens at arrival processing and again at re-implant processing. Pens of cattle were sampled 1 week after the second dose of vaccine and every 3 weeks for four test periods. Pair-matched pens of cattle were sampled concurrently. Test samples were seven ropes per pen hung overnight from the feed-bunk neck-rail (ROPES). Recovery of E. coli O157:H7 from at least one rope classified pens ROPES-positive. E. coli O157:H7 isolates were identified by standard biochemical methods and multiplex polymerase chain reaction. The probability for pens of cattle to test ROPES-positive was modeled using multilevel logistic regression with variance adjustment for clustering by matched pens and repeated measures. We studied 140 pens of cattle representing 20,556 cattle in 19 feedlots February through October 2004. Vaccinated pens of cattle were less likely to test ROPES-positive (OR = 0.59, p = 0.004). Because ROPES testing identifies organisms in the mouth of cattle, and the outcome is both associated with presence of the organism in the pen environment and correlated with the prevalence of fecal shedding, we conclude the two-dose vaccine regimen reduces the probability for environmental transmission of E. coli O157:H7 within commercial cattle feeding systems.

The aftermath of the Merck's HIV vaccine trial.

Abstract: The recently released results of the Merck's Phase IIb "test-of concept" vaccine trials have shown no protection from HIV-1 infection in the vaccinated group compared with a control group vaccinated with placebo. The study was designed to test the Merck's MRKAd5 trivalent candidate vaccine. The vaccine formulation was expected to stimulate a HIV-specific T cell immune response and to either prevent infection, or to reduce the levels of the viral load in vaccinated subjects. Upon the first evaluation of the interim data, the independent Data and Safety Monitoring Board (DSMB) underscored no protection from HIV-1 infection in the vaccine-inoculated volunteers compared with the control group; accordingly, the vaccine trial was stopped. This disappointing outcome warrants a critical analysis of the current vaccine studies and calls for a renewed effort toward a rational design of novel immunogens to be tested in large primate trials.

Hepatitis E: a neglected threat

Abstract: Hepatitis E, responsible for explosive waterborne outbreaks and sporadic cases of acute hepatitis in developing countries, affects predominantly young adults and has a fatality rate as high as 25% in pregnant women. No effective treatment exists for hepatitis E; however, a vaccine using a baculovirus-expressed recombinant hepatitis E capsid protein was recently studied in Nepal. In this review, the progress made in hepatitis E research and the recently concluded vaccine trial of the recombinant protein vaccine are briefly discussed.

HIV/AIDS vaccines: a need for new concepts?

Abstract: HIV vaccine research is at a crossroads carefully contemplating on the next path. The unexpected results of the Merck vaccine trial, while providing a stunning blow to a field in dire need of a protective vaccine, has also raised several fundamental questions regarding the candidate immunogen itself, preexisting immunity to vaccine vectors, surrogate assays and animal models used for assessing preclinical protective responses, as well as relevant endpoints to be measured in a clinical trial. As a result, the research community is faced with the daunting task of identifying novel vaccine concepts and products to continue the search. This review highlights and addresses some of the scientific and practical concerns.

The influenza matrix protein 2 as a vaccine target

Abstract: Matrix protein (M)2 is an Influenza A, type III membrane protein with an extracellular domain (ectodomain of M2 [M2e]) of 23 amino acid residues, which is strongly conserved across virus strains. M2 fulfills an important biological function in the life cycle of the Influenza A virus and has been a target of antiviral drugs. M2e has generated much interest as a potential vaccine target, and a clinical M2e vaccine trial was initiated in 2007. The advantage of M2e compared with hemagglutinin, the prime antigen target in conventional influenza vaccines, is that its sequence is conserved. This means that a stable, efficacious and easily produced M2e-based vaccine would provide protection not only against drifting seasonal influenza epidemic strains, but would also make it possible to vaccinate in anticipation of an emerging pandemic. Furthermore, most reported M2e-based vaccines are produced by economical and safe technologies. IgG subtype antibodies directed against M2e can prevent death from influenza and re...

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

Abstract: 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.

HIV vaccine trial no longer PAVEs the way.

Abstract: The National Institute of Allergy and Infectious Diseases (NIAID) decided recently to cancel plans for a large clinical trial of a candidate vaccine against HIV. The canceled clinical trial, known as PAVE 100, was originally proposed in January 2007 and designed to test whether the vaccine, which was developed by the NIAID’s Vaccine Research Center (VRC), could reduce acquisition of HIV infection and reduce viral load in those who became infected. However, PAVE 100 was put on hold even before it began enrolling volunteers and was then redesigned in May 2008 to reduce its scope after the failure of a similar vaccine made by Merck in a smaller clinical trial. Now Anthony Fauci, director of the NIAID, has decided to cancel the clinical trial altogether, saying that it was becoming clearer that more fundamental research and animal testing would be needed before an HIV vaccine was ever marketed (1). The candidate vaccine was to be administered using a prime-boost strategy, whereby individuals would be immunized three times with a priming DNA vaccine containing synthetic versions of four HIV genes (gag, pol, nef, and env) followed by a vaccine boost in the form of a weakened common cold virus (specifically adenovirus type 5 [Ad5]) carrying the same HIV genes. The vaccine boost element is similar to the vaccine developed by Merck, which was tested in a phase IIb clinical trial known as STEP — a multicenter, randomized, double-blind, placebo-controlled trial in which 3,000 participants in North America, South America, the Caribbean, and Australia received three doses of either vaccine (a mixture of three components, each consisting of a replication-defective Ad5 carrying a synthetic form of either gag, pol, or nef) or placebo. The STEP clinical trial was halted in September 2007 after interim analysis indicated that the vaccine did not work — it failed to reduce both acquisition of HIV infection and viral load in those who became infected. Subsequent analyses indicated that the vaccine made some individuals more susceptible to infection with HIV: more individuals who received the vaccine became infected with HIV than did recipients of the placebo. Although the vaccine itself was not responsible for the increased acquisition of HIV infection, it particularly increased the risk of infection in males who were both uncircumcised and had preexisting antibodies specific for Ad5. Given the similarity between the Merck vaccine and the vaccine boost portion of the VRC vaccine regimen, the original design of the PAVE 100 trial came under intense scrutiny from the AIDS Vaccine Research Subcommittee (AVRS), the group assisting the NIH in developing a comprehensive research program aimed at expediting the discovery and development of an HIV/AIDS vaccine. However, the scientists involved in PAVE 100 argued that much could still be learned from a clinical trial with their vaccine, and they scaled down the scope of their trial from 8,500 individuals in multiple international locations to 2,400 individuals in the United States. Furthermore, the redesigned PAVE 100 trial was to enroll just men who have sex with men, and only those both circumcised and with no measurable Ad5-specific antibodies at screening, and to focus on determining whether any immune correlates of decreased viral load could be detected in those who became infected during the course of the trial. When the redesigned PAVE 100 clinical trial was outlined at the May 2008 meeting of the AVRS, most members expressed support for the scaled-back trial (2). However, in announcing his decision, Fauci said that after meeting with scientists trying to understand why the Merck vaccine failed, he concluded that doing a large trial was not justified because scientists still do not understand many fundamental facts, such as which immune reactions are the most important in preventing infection with HIV (1). The NIAID will consider a much smaller and more focused trial designed to test whether the vaccine can markedly decrease viral load in individuals who become infected. “Show me that the vaccine works by lowering the amount of HIV in the blood,” said Fauci. “Then we will move to a larger trial that will document the link with a particular immune response” (1). A minority of researchers at the May 2008 meeting of the AVRS expressed concern that the VRC vaccine to be tested in the PAVE 100 clinical trial performed very similarly to the Merck vaccine in immunogenicity assays; one of the minority, John Moore (an HIV researcher at Weill Cornell Medical College), told the JCI that he agreed with the decision of the NIAID to cancel the vaccine trial. Other vaccine advocates, such as Seth Berkley, president and CEO of International AIDS Vaccine Initiative (IAVI), were quick to stress that “The decision by NIAID does not reflect paralysis in the AIDS vaccine field, or a lack of direction forward. In fact, it reflects the opposite. It reflects the dynamic learning that is the scientific process, that is pharmaceutical product development. The decision reflects leadership on the part of NIAID” (3). Berkley continued, “The AIDS vaccine field does not suffer from a lack of ideas about how to move forward . . . . There’s a lot of work going on and a lot more that needs to get done. We’re not at our destination, but we know the paths to follow” (3).

AIDS vaccine research: consider co-infections.

Abstract: In the News of the Week story “Trials of NIH's AIDS vaccine get a yellow light” (21 December 2007, p. [1852][1]), J. Cohen and B. Lester report on the NIH Vaccine Research Center (VRC) AIDS vaccine trial that was put on hold, and they discuss whether the initiative should be continued. The VRC AIDS vaccine is based on an adenovirus 5 (Ad5) vector similar to the Merck STEP vaccine for which the trial was halted earlier this year ([1][2]). The authors cite the arguments for and against continuing the VRC trial in a smaller group of participants that excludes people who have antibodies against Ad5. The arguments include ethical issues inherent in a vaccine with limited applicability and the lack of proven efficacy of the vaccine in preclinical research. We suggest another factor to consider in making this decision: The risk for the Ad5 seronegative participants to become infected with both HIV and Ad5 should be taken into account, especially in countries, such as Swaziland, where both viruses are highly endemic (seroprevalence 25% and 90%, respectively). 1. 1.[↵][3] 1. J. Cohen, 2. B. Lester , Science 318, 1852 (2007). [OpenUrl][4] [1]: /lookup/doi/10.1126/science.318.5858.1852a [2]: #ref-1 [3]: #xref-ref-1-1 "View reference 1. in text" [4]: {openurl}?query=rft.jtitle%253DScience%26rft.volume%253D318%26rft.spage%253D1852%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx

HIV/AIDS Vaccine Research

Abstract: The scale of the HIV epidemic in the last 25 years has been staggering: today there are 39.5 million people living with HIV, with more than 4 million new infections occurring every year (UNAIDS, 2006). The majority of new HIV infections worldwide occur in developing countries, where the brunt of the epidemic lies and one in four people are infected in the most severely affected regions. Many of them are young adults in their economically most productive years (UNAIDS, 2006). Here the scale of the pandemic threatens the very fabric of society. In tackling the burden of infectious diseases, effective vaccines are the only measure that has resulted not only in significant inroads into disease elimination and control but also disease eradication. While the best examples of vaccine successes are for viral infections such as polio and measles, vaccines against a range of other bacterial and viral pathogens have resulted in more than 98% reduction in diseases such as diphtheria, tetanus, Haemophilus influenza type b, measles, mumps, and rubella in the US and several other countries (Frazer et al., 2006). The quest for an HIV vaccine dates back more than 20 years, almost as long as the HIV pandemic itself, with the first HIV vaccine trial opening in August 1987 at the U.S. National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland (NIAID, 2005). Since then, successive candidates have reflected the growing understanding of HIV biology and immunology, and the field has expanded upon traditional vaccine approaches to meet the unprecedented challenges of HIV infection. This concerted effort in vaccine development is particularly critical in developing countries because of the staggering momentum of the epidemic.