Newsletter - Edition 26

New Generation Vaccines

An account of the Oxford Innovation Society Seminar chaired by Professor Adrian Hill, Head of the Oxford Institute of Molecular Medicine.

The development of new vaccines was the topic of the Oxford Seminar held at the Magdalen Centre in the Oxford Science Park on 2nd July 1998. The Oxford Seminars were established in 1995 in order to focus in more detail on some of the topics addressed at meetings of the Oxford Innovation Society. The aim of the Seminars is to promote interaction between academia and industry in order to identify areas for collaboration between the two communities. The Oxford Science Park, who shares these objectives with Isis Innovation Ltd, are sponsors of the Seminars and their support is gratefully acknowledged.

In his introduction the Chairman, Professor Adrian Hill of Oxford's Institute of Molecular Medicine (IMM), outlined the vital role which has been played by vaccines in combating the continuing scourge of infectious disease; estimates of the current annual global death toll are around 17 million, with TB and malaria being the principal causes and AIDS now poised to overtake them, especially in Africa and other developing nations. New generations of vaccines are essential in order to progress the vital role played by global immunisation programmes in reducing this loss of life. Most of the vaccines in current use rely on the very effective strategy of evoking a strong antibody response via the use of attenuated microorganisms or sub-unit vaccines. But, in order to tackle the many organisms which live inside cells, such as malaria, TB and HIV, it is necessary to stimulate the cellular arm of the immune response, in particular, cytotoxic T lymphocytes (CTL). This strategy, along with other approaches, such as the use of new vectors, the development of nucleic acid vaccines and the use of new devices such as the gene gun are typical of the methods which researchers in academia and industry are adopting in order to meet the challenge of improving the cost-effectiveness of public health intervention programmes based on mass vaccination.

Dr Gerald Voss, SmithKline Beecham Biologicals

The first novel vaccine approach to be described in detail was the use of adjuvant systems to induce and stimulate both humoral and cellular immunogenicity. The paper was presented by Dr Gerald Voss, of SmithKline Beecham Biologicals. He discussed three potential applications for the use of adjuvanted vaccines: HIV type 1, herpes simplex virus type 2 and malaria. The control of malaria, with its 1.5 to 3 million deaths a year in the developing world and up to 50,000 cases a year of travellers' malaria, is an important vaccine target and SBBio's approach is to try to block liver cell infection, one of the key stages in the life cycle of the malaria parasite, Plasmodium falciparum. Potent immune responses in animal models were induced using a variety of adjuvant systems in conjunction with recombinant proteins from the different human pathogens. Safety, immunogenicity and efficacy testing on humans followed and one adjuvant system showed particularly good results in the FDA-approved test. These findings have illustrated the usefulness of adjuvant systems in the design of vaccines for the prevention and possible treatment of a wide range of diseases.

Professor Andrew McMichael, University of Oxford Institute of Molecular Medicine

In the next paper, Professor Andrew McMichael described work at the IMM on progress towards an HIV vaccine. First identified fifteen years ago, HIV is now estimated to have infected more than 30 million people globally and AIDS has accounted for some 12 million deaths, 2 million of whom have been in sub-Saharan Africa. Despite much effort in research labs around the world, a successful HIV vaccine has proved elusive. It was thought that it should be an easy matter to make an antibody-inducing vaccine, but attempts using Gp 120 envelope vaccines were less effective than anticipated. The recently published Gp 120 structure has clarified why it will be difficult to produce an effective vaccine of this type.

The Oxford work has turned instead to an alternative approach, based on the role in the immune system played by the cytotoxic T lymphocytes (CTL), and the researchers' goal has been to make a vaccine which reliably induces a strong CTL response to HIV infection. Their tests have shown a high level CTL response using a string of epitopes encoded by DNA as the initial immunogen with a booster immunisation of the same epitope string in a modified vaccinia Ankara (MVA) viral vaccine. Trials followed with multiple vaccinations using primary immunisations with DNA delivered by a gene gun and booster immunisations with the recombinant MVA. Pronounced increases in CTL were observed post-immunisation, to a level comparable with those found in humans with HIV.

Dr Julian Hickling, Cantab Pharmaceuticals Research Limited

The disabling of a virus via the deletion of the gene which encodes the protein responsible for growth and cell infection was the topic of the paper presented by Dr Julian Hickling of Cantab Pharmaceuticals Ltd. Cantab have targeted the herpes simplex virus (HSV) market for their work. Genital herpes, caused by both HSV-1 and HSV-2, is a disease on the increase, with US statistics showing that during the period 1980 - 1990, between 25 million and 45 million were infected. One of the problems with controlling genital herpes is that only 20% of those infected have any symptoms; most are unaware of their condition and may continue to spread the disease. Dr Hickling's team found that if they deleted the gene encoding glycoprotein H and injected the disabled virus, it underwent only one round of replication, producing non-infectious progeny. The use of such a disabled infectious single cycle virus (DISC) combines the safety advantages of a killed vaccine with the immunogenic properties of a live virus vaccine.

Pre-clinical studies were followed by human trials, which showed good safety and immunogenic results. These clinical trials, which are partly complete, show that the DISC virus development shows great promise as both a prophylactic and a therapeutic approach to the control of genital herpes. Other exciting possibilities for DISC virus vaccines include enhancing the immunogenicity of tumour cells.

Professor Richard Moxon, University of Oxford Institute of Molecular Medicine

The meningococcus bacterium is the cause of a massive global public health problem; infections, particularly septicaemia and meningitis, occur in 1-2 individuals per thousand of the population of Europe during their lifetime and at a much higher incidence in Africa. The risk of rapid fatality or long term impairment of the central nervous system, especially of very young children, is one of the main reasons for the strenuous efforts being put into the development of safe and effective vaccines. Professor Richard Moxon described current research on the topic at Oxford's Institute of Molecular Medicine.

The three major meningococcous serogroups, A, B and C, can be differentiated by the chemical structure of their main virulence factor, the capsular polysaccharide. These entities have, to date, been the main target for the development of vaccines. Although the approach has been promising for Group A and C strains, targeting the polysaccharide has not proved a useful strategy for Group B, the serotype most common in Europe and the USA. Professor Moxon and his colleagues decided to look for an alternative candidate molecule and they studied both the protein polymers involved in the adhesion process and the lipopolysaccharide (LPS) of the meningococcus. The protein route, for which they initially had high hopes, proved unsuccessful but the LPS approach now looks much more promising. The genome sequence responsible for LPS synthesis has been identified and it is now possible to make a range of LPS mutants, to which monoclonal antibodies can be raised. The researchers are addressing the basic question of whether the inner core of the LPS is a valid target for vaccines and they are adopting a variety of strategies to meet the challenge of making such an entity immunogenic in humans.

Professor Gordon Dougan, Imperial College of Science Technology and Medicine

The delivery of vaccines through mucosal surfaces was discussed by Professor Gordon Dougan of Imperial College, London. This route is a safer alternative to the conventional method of inoculation via injection, and it offers the possibility of achieving a localised immune response, rather than the systemic response resulting from an injection. Professor Dougan and his team have been exploring the question of how the immune system discriminates between different antigens and they have investigated the various factors which contribute to the activation of the immune system. Problems specific to mucosal delivery have been identified and methods have been developed for overcoming them.

The researchers looked at a number of fused antigens, including herpes, diphtheria and typhoid, and they found in their studies on mice that pure proteins are not good at inducing a mucosal immune response. But using non-toxic derivatives of cholera-like enterotoxins as adjuvants, they found that the mucosal response could be enhanced. Another approach being explored by Professor Dougan is the use of live vaccine vectors such as salmonella. A description of the work being done on E. coli and tetanus models illustrated the progress being made in this area.

Professor Graham Rook, University College London Medical School

The programming of the human immune system was the topic of a paper given by Professor Graham Rook, of University College, London, Medical School. Evolution has encoded within the immune system certain information about the microbial and antigenic environment. This learning process in early life finely tunes the immune system to recognise antigens and respond appropriately. Professor Rook's hypothesis is that modern lifestyles and antibiotic use may be altering the pattern of inputs during the learning phase of the developing immune system. This may account for the observed increases in the incidence of allergies and autoimmunity and may even contribute to the increased occurrence of cancer.

There has been evidence to show that common and abundant environmental mycobacteria play a key role in the programming process; Professor Rook's research is based on this premise and he has conducted clinical trials on the use of immunogenic mycobacterial preparations as possible vaccines and adjuvants, with strikingly positive results. This new approach to the regulation and re-education of the immune system could have important implications for the development of vaccines and therapies for a variety of allergic and autoimmune disorders.

Dr Lee Roberts, PowderJect Pharmaceuticals plc

The final paper of the Seminar was given by Dr Lee Roberts, a scientist at the Madison, Wisconsin, laboratories of PowderJect Pharmaceuticals. His work has been on the development of DNA vaccines, based on plasmid constructs which encode only specific antigens expressed by pathogens. Such vaccines have a number of features which could make them very attractive; their specificity means that they are safer and more effective than vaccines based on attenuated viruses. Furthermore, they are easier and, therefore, cheaper to make.

Dr Roberts and his team have been studying the use of an intraepidermal gene gun to deliver plasmid DNA vaccines coated onto gold particles, rather than alternative delivery methods such as intradermal or intramuscular injection. They have been studying in particular the mechanisms which are involved in eliciting the immune response and have focused on the role played by the Langerhans cells (LC), which are the resident antigen-presenting cells in the epidermis. These cells capture and process antigens before they migrate to the lymph nodes and initiate an immune response by T-cells. The LC processing time was found to be about 24 hours.

The PowderJect research has concluded that the LC route is the principal of the three possible mechanisms by which DNA-vaccine encoded antigens are presented to T-cells and that gene gun delivery should allow the development of safer and improved vaccine administration.