Vaccine clinical trials

The FDA has set out guidance documents for grading toxicity in the conduct of clinical trials. The following is an adaptation from a recent document Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (2007). 

Nemunaitis J, Nemunaitis J. 2007. A review of vaccine clinical trials for non-small cell lung cancer. Exp Opin Biol Ther. 7 89-102. 

Schoen RT, Sikand VK, Caldwell MC, Van Hoecke C, GUlet M, Buscarino C, Parent DL. Safety and inununo-genicity profile of a recombinant outer-surface protein A Lyme disease vaccine clinical trial of a 3-dose schedule at 0,1, and 2 months. Clin Ther 2000 22(3) 315-25. 

Gershon AA, LaRussa P, Steinberg S. The Varicella vaccine. Clinical trials in immunocompromised individuals. Infect Dis Clin North Am 1996 10(3) 583-94. 

Kosten TR, Domingo CB, Hamon SC, Nielsen DA (2013) DBH gene as predictor of response in a cocaine vaccine clinical trial. Neurosci Lett 541 29-33... 

The website http //ClinicalTrials.gov contains the most complete and regularly updated list of ongoing cancer vaccine clinical trials. At the time of writing this chapter, cancer vaccines are represented by 782 entries in the database (including hematologic malignancies), 292 of which are open trials. This indicates a continued interest in cancer vaccines, possibly encouraged by some of the obvious successes, such as ACT, which clearly demonstrate the enormous power of the immune system to combat cancer. 

Schiller, J. T. Castellsague, X. Villa, L. L. Hildesheim, A., An update of prophylactic human papillomavirus LI virus-like particle vaccine clinical trial results. Vaccine 2008, 26, (Supplement 10), K53-K61. 

Until now only the saponin adjuvant QS-21 (3) has entered vaccine clinical trials. Saponin mixtures causing local toxicity and hemolytic activity such as Quil A, have not yet been tested in clinical trials of human vaccines. After preclinical trials of QS-21 in rabbits, dogs, rhesus monkeys and baboons, this molecule was evaluated in phase 1 clinical trials of experimental melanoma immunotherapeutic vaccines, of HIV-1 subunit vaccines and more recently of a promising malaria vaccine [34-36]. 

Live attenuated vaccines for RSV are also being developed. Most of these vaccine candidates are derived from cold adaptation, by passing the vims at progressingly lower temperatures than human body temperatures. However, other means of mutagenesis have been used to generate vaccine candidates (72). Several clinical trials of these vaccines are also in progress (73,74). 

Parainfluenza. Parainfluenza vimses (PIV) also causes viral pneumonia in infants. It is similar to RSV, therefore similar approaches are being used for developing a vaccine. A five attenuated PIV-3 vaccine has been in clinical trial (74). 

Vaccine candidates are based on the two viral surface proteins, gD and gB (80). Recombinant methods are used to express the proteins, either in Chinese hamster ovary (CHO) cells or in baculovims. The proteins are purified as subunits and formulated with different adjuvants. Clinical trials with these vaccine candidates have been performed, but the results to date have not been encouraging. 

Influenza. Although current influenza vaccine (subunit spHt vaccine) has been in use yearly for the elderly, it is not recommended for the general population or infants. Improvements to increase or prolong the immunogenicity, reduce the side-effects (due to egg production procedure), and provide mass protection are stiU being pursued. One approach is to use a five, attenuated vims though cold adaptation. A vaccine has been used in Russia and demonstrated to be safe and efficacious for infants (82). Clinical trials for a similar vaccine are being carried out in the United States (83). 

One of the early vaccine candidates was directed against sporo2oites, the form of the parasites that is first injected into the host by a mosquito. With recent development of recombinant techniques, several circumsporo2oite proteins or its related peptides were proposed as the vaccine candidates. Clinical trials have been carried out. The vaccines were immunogenic, but did not provide sufficient protective efficacy (90,91). 

Interest in vaccine development has centered around the asexual erothrocytic stage of the life cycle, especially the mero2oite. Several proteins associated with these stages have been identified and produced by recombinant techniques (92,93). The most prominent is the MSA-1 protein of the mero2oite. A clinical trial with this protein is being planned (93). 

Adjuvants are substances which can modify the immune response of an antigen (139,140). With better understanding of the functions of different arms of the immune system, it is possible to explore the effects of an adjuvant, such that the protective efficacy of a vaccine can be improved. At present, aluminum salt is the only adjuvant approved for use in human vaccines. New adjuvants such as QS-21, 3D-MPL, MF-59, and other liposome preparations are being evaluated. Several of these adjuvants have been in clinical trial, but none have been approved for human use. IL-12 has been proposed as an adjuvant which can specifically promote T-helper 1 ceU response, and can be a very promising adjuvant for future vaccine development. 

Development of a peptide vaccine is derived from the identification of the immunodominant epitope of an antigen (141). A polypeptide based on the amino acid sequence of the epitope can then be synthesized. Preparation of a peptide vaccine has the advantage of allowing for large-scale production of a vaccine at relatively low cost. It also allows for selecting the appropriate T- or B-ceU epitopes to be included in the vaccine, which may be advantageous in some cases. Several vaccines based on peptide approaches, such as SPf66 (95) for malaria and an HIV-1 peptide (142) have been in clinical trials. No peptide vaccines are Hcensed as yet. 

A large and rapidly growing number of clinical trials (phase I and phase II) evaluating the potential of DNA vaccines to treat and prevent a variety of human diseases are currently being performed ( http // clinicaltrials.gov) however, there is yet no licensed DNA vaccine product available for use in humans. The clinical trials include the treatment of various types of cancers (e.g., melanoma, breast, renal, lymphoma, prostate, and pancreas) and also the prevention and therapy of infectious diseases (e.g., HIV/ABDS, malaria, Hepatitis B vims, Influenza vims, and Dengue vims). So far, no principally adverse effects have been reported from these trials. The main challenge for the development of DNA vaccines for use in humans is to improve the rather weak potency. DNA vaccines are already commercially available for veterinary medicine for prevention of West Nile Vims infections in horses and Infectious Hematopoetic Necrosis Vims in Salmon. 

Liu MA, Ulmer JB (2005) Human clinical trials of plasmid DNA vaccines. Adv Genet 55 25-40... 

Several TLR-4 adjuvants for vaccines have been developed to date. An example of these is monopho-sphoryl lipid A (MJPL) a modified version of lipid A found in LPS [4]. It has been used extensively in clinical trials as it is far less toxic than LPS. It is hoped to use MPL in vaccines against infectious diseases, allergies and cancer. Derivatives of MPL have now been... 

More than 40 medications have been investigated but none have shown consistent efficacy for primary cocaine or amphetamine dependence. These medications include dopaminergic agonists, antidepressants, and more recently disulfiram, selegiline, and a cocaine vaccine (see Table 5—2 for summary). Studies have been relatively brief and have focused on abstinence initiation rather than on relapse prevention, but even these modest treatment goals have not been attained. The focus in the discussion that follows is on pharmacotherapies for cocaine dependence, because very few clinical trials have been completed with amphetamine-dependent patients. Furthermore, none of the studies of amphetamine dependence have shown results different from those described for cocaine dependence (Rawson et al. 2002b Srisurapanont et al. 2001). 

Once a suitable strain is available, the prachce is to grow, often ftom a single organism, a sizeable culture which is distributed in small amounts in a large number of ampoules and then stored at 70°C or freeze-dried. This is the seed lot. From this seed lot, one or more ampoules are taken and used as the seed to originate a limited number of batches of vaccine which are first examined exhaustively in the laboratory and then, if found to be satisfactory, tested for safety and efficacy in clinical trials. Satisfactory results in the clinical trials validate the seed lot as the seed from which batches of vaccine for routine use can subsequently be produced. 

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