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PubMed2006

Statistical considerations for noninferiority/equivalence trials in vaccine development.

Noninferioritylequivalence designs are often used in vaccine clinical trials. The goal of these designs is to demonstrate that a new vaccine, or new formulation or regimen of an existing vaccine, is similar in terms of effectiveness to the existing vaccine, while offering such advantages as easier manufacturing, easier administration, lower cost, or improved safety profile. These noninferioritylequivalence designs are particularly useful in four common types of immunogenicity trials: vaccine bridging trials, combination vaccine trials, vaccine concomitant use trials, and vaccine consistency lot trials. In this paper, we give an overview of the key statistical issues and recent developments for noninferioritylequivalence vaccine trials. Specifically, we cover the following topics: (i) selection of study endpoints; (ii) formulation of the null and alternative hypotheses; (iii) determination of the noninferioritylequivalence margin; (iv) selection of efficient statistical methods for the statistical analysis of noninferioritylequivalence vaccine trials, with particular emphasis on adjustment for stratification factors and missing pre-or post-vaccination data; and (v) the calculation of sample size and power.

Endpoint Determination↗
PubMed2003

A highly infective Plasmodium vivax strain adapted to Aotus monkeys: quantitative haematological and molecular determinations useful for P. vivax malaria vaccine development.

The New World primate Aotus nancymaae is susceptible to infection by the human malaria parasite Plasmodium vivax and has therefore been recommended by the World Health Organization as a model for malaria vaccine candidate evaluation. We report the isolation, adaptation, titration and genetic characterization of a P. vivax wild strain in splenectomized A. nancymaae monkeys. Parasitemia remained high after 22 passages, reaching 7.88% by Giemsa and Acridine Orange staining and Real-Time PCR determination, making this P. vivax strain a highly infective and reliable asset to be used in P. vivax biological studies and vaccine development.

Animals↗
PubMed1983

Immune responses to viral antigens in man and their relevance to vaccine development: memorandum from a WHO meeting.

A meeting of an informal working group on immune responses to viral antigens was convened in Amsterdam on 15-18 November 1982 to discuss recent developments in this field and to formulate proposals for international collaborative studies relevant to the needs of the WHO Programme on Vaccine Development. The meeting concluded that the time was ripe for collaborative studies on a wide range of aspects of the immune responses to viral antigens in man. Areas for collaborative effort were defined. These included (a) the role of virus-specific cytotoxic T lymphocytes in virus clearance following infection, (b) correlation of changes in natural killer cells and virus replication, virus virulence, and induction of cytotoxic T lymphocyte, (c) induction of interferons and other mediators of immune responses, and (d) role of individual viral antigens in immune responses. This Memorandum summarizes the discussions and recommendations of the group.

Antibodies, Viral↗
PubMed1987

Naturally acquired antibodies to sporozoites do not prevent malaria: vaccine development implications.

The first human vaccines against the malaria parasite have been designed to elicit antibodies to the circumsporozoite protein of Plasmodium falciparum. However, it is not known whether any level of naturally acquired antibodies to the circumsporozoite protein can predict resistance to Plasmodium falciparum malaria. In this study, 83 adults in a malaria-endemic region of Kenya were tested for circumsporozoite antibodies and then treated for malaria. They were monitored for the development of new malaria infections for 98 days. Antibody levels, as determined by four assays in vitro, were indistinguishable between the 60 individuals who did and the 23 who did not develop parasitemia during follow-up, and there was no apparent relation between day of onset of parasitemia and level of antibodies to circumsporozoite protein. Unless immunization with sporozoite vaccines induces antibodies that are quantitatively or qualitatively superior to the circumsporozoite antibodies in these adults, it is unlikely that such antibodies will prevent infection in areas with as intense malaria transmission as western Kenya.

Adult↗
PubMed2002

Vaccine development against Neospora caninum infection.

Neospora caninum is a recognized protozoan parasite of a wide range of mammalian hosts, and was reported for the first time in 1988. The isolation of its oocysts in dog's faeces in 1998 led to its establishment as a parasitic species undergoing typical coccidian life cycle. Infection with N. caninum causes paralysis and death in young livestock and companion animals, and is associated with abortions and stillbirth in cattle, and neurologic disease in calves. Considering the economic and agricultural importance of neosporosis, there is the urgent need to develop biological control measures aimed at preventing its transmission, infection, as well as reducing severity of the disease. In this paper, we have reviewed the progress made to date on the parasite-host immunology and on vaccine development including its prospects, and discussed possible strategies in the formulation of vaccine(s) against neosporosis.

Animals↗
PubMed1999

T lymphocyte responses in HIV-1 infection: implications for vaccine development.

Substantial progress has been made over the past year in understanding the cellular immune response in HIV pathogenesis. Cytotoxic T lymphocytes play a critical role in establishing the level of viremia and virus-specific Th cell responses appear to affect the in vivo efficacy of cytotoxic T lymphocytes. Together, these new data provide important insights to refocus efforts aimed at immunotherapeutic interventions and vaccine development.

AIDS Vaccines↗
PubMed1987

Sequence variation in putative functional domains of the circumsporozoite protein of Plasmodium falciparum. Implications for vaccine development.

Sequences of the circumsporozoite protein gene from five isolates of the human malaria parasite Plasmodium falciparum are compared, and the extent of sequence variability within putative functional domains is assessed in terms relating to vaccine efficacy. Nucleotide substitutions were observed outside of the immunodominant domain. Of the substitutions observed outside of the repeat domain, none were silent. The substitutions correlated with biologically functional regions, such as a helper T cell epitope (Th2R) and a region (N1) which may be important in liver invasion. Contrary to previous impressions, the small numbers of amino acid changes in these areas of the protein seem potentially very significant. The immunodominant repeat region displays several characteristics that implicate a rapid evolutionary mechanism, most probably involving recombination. The data supporting this are 1) variable numbers of repeats, 2) a shifting pattern of substitutions among the isolates, and 3) codon bias. The region thus has the potential for very rapid change should an effective anti-repeat vaccine come into use. We conclude that strain variability is significant, that the potential for large scale variation in the repeats is great, and that regions that may be critical for an effective vaccine are polymorphic. Their potential impact on malaria vaccine development must be addressed.

Animals↗
PubMed2006

Challenges for cancer vaccine development.

The first generation of human cancer vaccines has been tested in phase III clinical trials, but only a few of these have demonstrated sufficient efficacy to be licensed for clinical use. This article reviews some of the mechanisms that could contribute to these limited clinical responses, and highlights the challenges faced for development of future vaccines.

Animals↗
PubMed2005

Prevention of Staphylococcus aureus infections: advances in vaccine development.

Staphylococcus aureus is a ubiquitous bacterial species that causes serious disease in a minority of carriers, particularly in hospital settings. S. aureus disease is difficult to treat, and antibiotic-resistant strains have become common. Prevention of S. aureus disease would therefore be the best way to limit the morbidity and mortality caused by this organism, but its virulence is determined by a number of different factors, making design of a widely effective vaccine difficult. Here, various S. aureus virulence factors and attempts to develop vaccines or other protective drugs based on these factors are reviewed. In particular, the results of a Phase III clinical study of a vaccine directed at capsular polysaccharides types 5 and 8 are discussed.

Animals↗
PubMed2002

The past, present and future of HIV-vaccine development: a critical view.

Despite the extensive efforts that have been made to combat AIDS, the global number of HIV-1 infections is still increasing. There is major consent among scientists worldwide, that the development of successful HIV vaccine strategies requires a profound understanding of the epidemiological principles of a viral pandemic, as well as deep insights into the molecular and immunological mechanisms of HIV pathogenesis. This review provides an overview of past and present developments, as well as future aspects of HIV vaccines, and also provides a summary of current clinical trials in man.

AIDS Vaccines↗
PubMed1992

Future perspectives for vaccine development.

The successful development of an anti-fertility vaccine necessitates overcoming obstacles in eliciting an immune response to self species body constituents. The feasibility of accomplishing this task has been demonstrated for certain antigens described in this workshop; however, additional vaccine candidate antigens may yet be revealed from the application of recent advances in molecular biology. Improvements in vaccine design are likely to occur from discovery of more appropriate epitopes on targeting antigens, new carrier molecules for terminating immunological tolerance, expression of vaccine antigens in suitable live vectors, the co-immunization with more than one antigen, the use of safer and/or more effective adjuvants and vehicles, more efficient immunization by targeting antigens to specific lymphoid cells, and the development of superior vaccine delivery systems. Research directed to restricting the immune response to the genital tract and to intentionally reverse the effects of immunization will likely be pursued in the future. All of these areas need to be addressed if vaccines are to be developed that are not only safe and effective but also highly acceptable as birth control methods.

Animals↗
PubMed2005

Tuberculosis vaccine development; from mouse to man.

A tuberculosis (TB) vaccine candidate, Mtb72, was developed following an antigen discovery program involving a combination of expression cloning strategies and evaluation of human immune responses. Adjuvant selection was also performed, resulting in the prioritization of AS02A and AS01B, and an industrial process for vaccine production was developed. Safety, immunogenicity, and protection studies in mice, guinea pigs, rabbits, and monkeys supported the initiation of clinical development of Mtb72f in AS02A.

Adjuvants, Immunologic↗
PubMedDate not supplied

Cholera toxin genes: nucleotide sequence, deletion analysis and vaccine development.

Nucleotide sequence and deletion analysis have been used to identify the regulatory and coding sequences comprising the cholera toxin operon (ctx). Incorporation of defined in vitro-generated ctx deletion mutations into Vibrio cholerae by in vivo genetic recombination produced strains which have practical value in cholera vaccine development.

Base Sequence↗
PubMed2001

Leishmaniasis: current status of vaccine development.

Leishmaniae are obligatory intracellular protozoa in mononuclear phagocytes. They cause a spectrum of diseases, ranging in severity from spontaneously healing skin lesions to fatal visceral disease. Worldwide, there are 2 million new cases each year and 1/10 of the world's population is at risk of infection. To date, there are no vaccines against leishmaniasis and control measures rely on chemotherapy to alleviate disease and on vector control to reduce transmission. However, a major vaccine development program aimed initially at cutaneous leishmaniasis is under way. Studies in animal models and humans are evaluating the potential of genetically modified live attenuated vaccines, as well as a variety of recombinant antigens or the DNA encoding them. The program also focuses on new adjuvants, including cytokines, and delivery systems to target the T helper type 1 immune responses required for the elimination of this intracellular organism. The availability, in the near future, of the DNA sequences of the human and Leishmania genomes will extend the vaccine program. New vaccine candidates such as parasite virulence factors will be identified. Host susceptibility genes will be mapped to allow the vaccine to be targeted to the population most in need of protection.

Animals↗
PubMed2001

Baboons as an animal model for human immunodeficiency virus pathogenesis and vaccine development.

Baboons (Papio cynocephalus) provide a valuable animal model for the study of human immunodeficiency virus (HIV) pathogenesis because HIV-2 infection of baboons causes a chronic viral disease that progresses over several years before clinical signs of acquired immunodeficiency syndrome (AIDS) appear. Since HIV-2-infected baboons develop a chronic viral infection, insights into the immuno-biology of viral latency, clinical stages of disease, virus infection of lymphatic tissue and HIV transmission can be gained using this animal model. The development of an AIDS-like disease in baboons is viral isolate and baboon subspecies dependent. Thus, viral virulence factors and host resistance can be studied as well as the mechanisms of innate and acquired immunity. The control of virus infection is dependent upon cytotoxic and non-cytotoxic antiviral activity of CD8+ T cells. In this regard, some of the HIV-2-infected baboons develop potent antiviral cellular immune responses that have a similar magnitude to that found in HIV-1-infected long-term survivors (or non-progressors). In our laboratory, baboons have been used to study DNA vaccine strategies using new cationic liposome formulations and granulocyte macrophage-colony stimulating factor and B7-2 as genetic adjuvants. The results demonstrate the value of using baboons as an animal model of AIDS pathogenesis and vaccine development.

AIDS Vaccines↗
PubMed1994

NIH conference. HIV vaccine development: a progress report.

The development of a safe, effective preventive vaccine for human immunodeficiency virus (HIV) infection remains an area of vigorous research. Several highly innovative vaccine candidates are being developed, and more than 13 vaccine candidates have been tested in human phase I or II trials. All have produced antibody and several have produced modest neutralizing titers, but to date no reproducible evidence has suggested prolonged, high-titer neutralization across a diversity of HIV strains. Furthermore, only the live recombinant vector approaches have produced some evidence of cytotoxic T-cell responses. The principal obstacle to progress is the lack of definitive information on what constitutes a protective immune response. There is no animal model for HIV-induced disease. Hence, the identification of the correlates of immunity and more useful animal models is among the highest priorities for HIV vaccine research. Large-scale efficacy trials raise daunting scientific, ethical, and resource issues. Nonetheless, preparation in such trials is underway in order to be in a position to evaluate the most promising vaccine candidate.

AIDS Vaccines↗
PubMed2006

HIV vaccines: new frontiers in vaccine development.

A human immunodeficiency virus (HIV) vaccine is the most promising and feasible strategy to prevent the events during acute infection that simultaneously set the course of the epidemic in the community and the course of the disease for the individual. Because safety concerns limit the use of live, attenuated HIV and inactivated HIV, a variety of alternate approaches is being investigated. Traditional antibody-mediated approaches using recombinant HIV envelope proteins have shown no efficacy in 2 phase III trials. Current HIV vaccine trials are focusing primarily on cytotoxic T lymphocyte-mediated products that use viral vectors, either alone or as boosts to DNA plasmids that contain viral genes. The most immunogenic of these products appear to be the recombinant adenovirus vector vaccines, 2 of which are now in advanced clinical development.

AIDS Vaccines↗