The Pharmaceutical Journal
Vol 269 No 7216 p398-399
21 September 2002

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World Congress of Pharmacy and Pharmaceutical Sciences summary

New vaccines and vaccine approaches — developments and challenges

Recent developments and upcoming challenges in the area of vaccines and vaccination was the subject of a symposium organised by FIP's board of pharmaceutical sciences on 2 and 3 September.

Opening the session, Professor Paul Henri Lambert, Centre of Vaccinology, University of Geneva, Switzerland, said: "We are overloaded with vaccines." He explained that children receive around 20 different vaccines before the age of six years, including DTP Hib, polio and BCG, and vaccine safety is a key issue.

There have been, he explained, allegations that vaccines can trigger autoimmune reactions. For example, association has been demonstrated between post rabies vaccine and encephalitis, as well as MMR/measles vaccines and thrombocytopenia. In several countries allegations have not been proved, eg, associations between hepatitis B and multiple sclerosis in France, MMR and irritable bowel syndrome/autism in Britain, and Hib/other infant vaccines and type 1 diabetes in the United States. Professor Lambert emphasised that more attention should be paid to the immune mechanism during research and development work. Monitoring of autoimmune reactions during clinical trials could prevent post-marketing allegations.

Mucosal immunisation

Professor Jiri Mestecky, United States, suggested the "dream vaccine" should be safe, inexpensive, heat stable, given orally, effective in young children and the elderly, single dose, multiple disease, useful for mass immunisation and induce systemic and mucosal immunity.

Most infectious agents enter through mucosal surfaces; these contain the largest accumulation of lymphoid cells. Mucosal and systemic immune components are largely independent of each other. The magnitude and quality of immune response via mucosal delivery depends on the immunisation site, antigen delivery system and differences between species (eg, mouse versus man). Mucosal immunisation routes include oral, nasal, rectal and vaginal. Intranasal immunisation have shown promising results in mice and humans. The disadvantage is difficulties in paediatric administration and high dose variability. Oral vaccines currently use salmonella, E coli, BCG or poliovirus as the live vector. The problem with using live vectors via the oral route is competition with the normal mucosal microflora; therefore, dose concentrations have to be high. Salmonella is the most commonly employed live vector. Pre-existing immunity to salmonella may, however, decrease the immunogenicity of the desired antigen. Another promising vector for mucosal administration is vaccinia virus. It is inexpensive, heat stable and facilitates insertion of 10 to 20 genes. Mucosal administration to mice induces serum IgG, mucosal IgA and cytotoxic T lymphocyte activity. Vaccinia is destroyed in the stomach (so requires enteric coating) and induces oral lesions (so cannot be administered via the oral route).

Mucosal DNA vaccines are easy and inexpensive to manufacture. They induce a response in mucosal and systemic immune components but a suitable delivery system is still needed. DNA vaccines currently under investigation include HIV, retrovirus, measles and malaria. Plants can been used to produce antigens for active immunisation. Tobacco, potato, peas, lettuce, banana and tomato are commonly used. Professor Mestecky referred to current work on vaccines via foods. When asked about food rotting, he replied that (freeze-dried) tomatoes and potatoes look most promising. Bananas are not suitable because they do not express the antigen well.

One issue is tolerance. Tolerance can be seen in areas such as the oral cavity. Split tolerance may occur and humans may develop tolerance to antigens over time. The subject of foods as a delivery method for pharmaceuticals is under discussion in the US.

'Flu vaccines — transcutaneous and intranasal delivery systems

A transcutaneous delivery system for influenza vaccination was described by Dr Gregory Glenn, IOMAI Corporation, US. It consists of a small, thin, immunostimulant patch that is easy to manufacture and comfortable to wear. The time of wear can be relatively brief because the dose is delivered quickly. There is no need to wear the patch overnight. The patch has advantages for the elderly, immunocompromised and needle-phobic. It is dose sparing and a safe delivery method for potent antigens/adjuvants. The patch uses the numerous Langerhans cells in the skin as a safe transport mechanism. Large proteins can be introduced via this mechanism if they target Langerhans cells. The patch should be placed near the normal injection site. To date, the only administration site investigated is the arm. CT4, CT8 and T cell studies have been conducted and there is an indication that B cell memory is induced. The patch is currently undergoing phase II clinical trials.

Dr Reinhard Glueck, director of research and development, Berna, Switzerland, spoke about his experiences with Nasaflu, the first nasal 'flu vaccine to be licensed (not marketed). It consists of influenza antigen and E coli as adjuvant. The spray is held horizontally and two sprays are given in each nostril one week apart. Following pre-clinical testing on ferrets, toxicology studies were performed on mice. Field trials on 250 adults and 250 children showed 85 per cent and 90 per cent protection against flu, respectively. The major drawback reported is the occurrence of Bell's palsy in Switzerland during 2000/01 — 10 incidences during clinical trials, 13 post marketing and 23 in one ENT clinic alone. Ninety-one per cent of cases recovered fully but there was high variation in the latency period from two to 80 days. The causal relationship is therefore unclear. The geographical distribution of cases also does not match high sales volume areas. Further studies are now being conducted to investigate possible association and the spray is being reformulated with one less adjuvant. This will result in a lower immune response but, it is hoped, a safer vaccine.

Prime-boost strategies in malaria

Dr Sarah Gilbert, research associate, Oxford University, UK, explained the current status of malaria vaccines. Her research group wanted to develop a vaccine that stimulated strong T cell responses against antigens expressed during the liver stage of malarial infection. This should then prevent infection of blood and malaria transmission. The immunisation sequence is critical for protection. Various combinations were tried with disappointing results. Finally, combination of DNA prime + MVA (Modified Vaccinia Virus Ankara) boost exhibited 100 per cent protection.

Malaria vaccine trials have been conducted in the UK and Gambia; preliminary results confirm the vaccine is effective, delaying (and reducing) the number of parasites appearing from the liver by two days. However, it is not totally protective. Another possible vector under trial is fowlpox virus FP9. Pox viruses do not depend upon cold chain maintenance, which is an advantage in hot climates. FP9 prime + MVA boost has shown complete protection and maintenance for up to six months. Future clinical trials and field work in the Gambia will compare DNA and FP9 as priming agents. Dr Gilbert could not specify how soon the vaccine would be available. A single delivery system is needed rather than the current double system to aid compliance. Measurement of memory is highly empirical at present. Polysaccharide boost after one year gives an indication of B cell memory. At T cell level, there is no access to human lymphoid tissue.

Other prime-boost trials currently taking place in Oxford using DNA-MVA are HIV, hepatitis B and melanoma. BCG-MVA administration via the nasal mucosa is being investigated for a tuberculosis vaccination as nasal administration provides better lung protection than parenteral administration.
—Contributed by Sonia Sanghani.