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FIP 2008: What is happening in the world of vaccine development and why

A science session at the 2008 World Congress of Pharmacy andPharmaceutical Sciences looked at why alternate routes for vaccineadministration are needed and highlighted some of the work that hasbeen done to create and formulate these much needed alternatives.Developers also need to consider the effects of war and poverty.Lin-Nam Wang reports

by Lin-Nam Wang

A science session at the 2008 World Congress of Pharmacy and Pharmaceutical Sciences looked at why alternate routes for vaccine administration are needed and highlighted some of the work that has been done to create and formulate these much needed alternatives. Developers also need to consider the effects of war and poverty. Lin-Nam Wang reports

 

In 2005, the European Union put out a strategic position on HIV vaccine development. It said: “There has been minimal global effort for clinical trial assessment of vaccine approaches that have the potential to protect at mucosal surfaces during early events.”

But why would you want to give a vaccine mucosally, for example, via the lungs?

Gerrit Borchard, from the laboratory of pharmaceutics and biopharmaceutics at the University of Geneva, Switzerland, who has been working on mucosal vaccines, explained that although mucosal surfaces are ports of entry for a multitude of pathogens, they also contain a large number of lymphocytes — something like 6x1010 antibody producing cells.

This means that with a mucosal vaccine, the immune response is both local and systemic, rather than just systemic as achieved with injected vaccines.

“You get quite a nice first line of defence against infection with pathogens. You avoid infection — you avoid the entry of the pathogen into the body — whereas with parental application, in most cases, you manage the infection after the pathogen has entered the body,” he said.

A second reason for looking into the use of mucosal vaccines came from work published in Nature Immunology, which looked at the changing paradigm of HIV infection. The conventional view is that, looking at immune competence from primary infection, T-cell levels steadily decrease as the disease develops, until the establishment of AIDS. The new view is that immune competence is lost much more rapidly after primary infection.

A possible explanation for this new model is that mucosal T-cells have a role in HIV infection: the virus infects a subset of mucosal T-cells leading to rapid depletion of these cells due to lytic viral replication. Functional and structural degradation of mucosal tissue results in increased antigen exposure, which, in turn, results in opportunistic infections.

These opportunistic infections further activate the same subset of T-cells, leading to a vicious circle. “Maybe in HIV we are looking at the wrong spot for the T-cell and what we should be looking into is the mucosal side, rather than the blood side of T-cells,” Professor Borchard said.

In addition, mucosal tissues are interconnected by the common mucosal immune system. “This means that if you induce an immune response at one mucosal site, you have a chance to also induce a response at distal mucosal sites in the body, for example the gastrointestinal-associated lymphatic tissue, the bronchi-associated lymphatic tissue, the nasal-associated lymphatic tissue and the genital tract,” he said.

The EU has also said that strategies are needed that could elicit mucosal immune responses in addition to systemic immune responses. This means that we need to develop delivery systems to get vaccines to the site of action (mucosal surfaces) and this could be attractive to pharmaceutical technologists and pharmacists, he added.

Ideal vaccines overcome war and poverty

Gerrit Borchard: in the real world injections present risk of infections

Professor Borchard then turned to the characteristics of an ideal vaccine, explaining the SAFE concept. First, the vaccine must be stable under harsh environmental conditions. For example, in Kenya, a vaccine might have to be transported by bicycle to the last village in a region in order to achieve full coverage.

Second, the vaccine must be affordable in order to allow large scale vaccination campaigns in developing countries. “I’m talking about $1 per tablet or 50c per shot [being] all these countries can afford. Otherwise they won’t do it,” he said.

Third, the vaccine must be fast — “preferably a single shot and probably a depot vaccine or pulsatile release to expose the body to longer periods of antigen”. Such vaccines can also increase compliance.

Some people, particularly teenagers, may find having to go to a vaccination point boring and do not go back. Moreover, in some parts of Asia, such as Vietnam and Cambodia, people are having to travel over heavily land mined areas — people are risking their legs in order to come to vaccination points, he added.

And, lastly, the vaccine must be easy to apply. It should be nasal, topical, oral or pulmonary in order to avoid parenteral administration and its associated risks.

Professor Borchard then took a closer look at delivery systems for vaccines. Alternatives to injections would mean better immunogenicity (immunity at the correct site and earlier and stronger immunity) and improved safety, access and compliance.

Logistics would also be simpler, with reduced need for a cold chain and, perhaps, medical professionals. In particular, he highlighted the burden of disease associated with contaminated healthcare injections. For example, 32 per cent of cases of hepatitis B virus infection in developing countries is attributable to the use of non- sterile syringes and needle sharing.

“For us, this is an argument for the use of vaccines that are applied mucosally,” he said. The safe removal of used needles in these countries is also an issue for the structure of vaccination campaigns, he added.

Alternative delivery systems include jet (needle-free) injectors, microneedles and oral, nasal, pulmonary or transcutaneous delivery formulations. Work is also being done on ballistic delivery — a gene gun approach.

Oral delivery is suitable for live enteric vaccines and is easy to achieve. For example, it is used for polio, and a rotavirus oral vaccine has recently been introduced to the market. However, there are significant barriers to this mode of delivery, he said, including that the vaccine is exposed to acids, enzymes and commensal bacteria in the gastrointestinal tract, Professor Borchard said.

There is also a risk of immunological tolerance and a large quantity of antigen is probably needed in order to achieve the required result. Furthermore, formulation can be an issue.

There are fewer biological barriers to nasal delivery and nasal spray devices are widely used, but non-live vaccines can require an adjuvant and this may add to cost. There has already been some success with these types of vaccine, for example, Flumist in the US but Professor Borchard also noted the recent withdrawal of a Swiss nasal flu product (Berna Biotech) from the market.

In addition, he said that although these types of vaccine may be easy to use in infants, in places like subSaharan Africa, where upper respiratory tract infections are common, the efficacy of nasal vaccines could be challenged by a runny nose or clogged airways.

Nevertheless, there have been good results from large scale studies in Mexico and South Africa with nasal measles vaccines. These are inexpensive and can be used by trained non medical staff, although Professor Borchard noted that if you talk to companies about pulmonary vaccination, there are always concerns about safety and these types of vaccines may be associated with pneumonia.

Professor Borchard also touched on the global situation of infectious diseases. “The annual death toll by infectious diseases is 17 million, with HIV being the biggest killer followed by tuberculosis and malaria,” he said. Focusing on tuberculosis, he said that two billion people are infected, with 10 per cent morbidity.

This is not just a problem for the developing world, he warned, noting that the pharmacy in Geneva, where his wife works, currently has patients with TB, one with multidrug-resistant infection.

The advantages, therefore, of mucosal vaccination are:

  • Better patient compliance and safety
  • No need for qualified personnel
  • No need for cooled storage and transport
  • Beating the antigen at the site of entry

Looking at the science of these vaccines in more detail, Professor Borchard explained that in the gastrointestinal tract, antigens can be seen with a microscope passing through Peyer’s plaques in the lumen. M cells take up (“sample”) the antigen.

This also works in other mucosal tissue and in vitro models that demonstrate dendritic cell sampling (dendritic cells being important antigen presenting cells in mucosal tissue) have been made. He ended by giving two examples of work done on mucosal vaccines at the University of Leiden, The Netherlands.

The first involved diptheria toxin loaded onto microparticles to look at oral immunisation in mice. Different doses were used and the IgG and IgA responses were studied. It was found that the association of the toxin with chitosan microparticles enhances the mucosal and systemic immune response, and protective immunity against Corynebacterium diptheriae was induced.

The second was the development of tuberculosis (TB) DNA pulmonary vaccines (the vaccines carry the information about certain antigens of the pathogen), in association with the Pasteur Institute, Belgium.

Professor Borchard reminded delegates that, currently, the only vaccine against TB is Bacille Calmette-Guérin, which has several disadvantages, including that it fails to protect against pulmonary TB in adults and that it cannot be given to immunodeficient patients (so it cannot be used in those infected with HIV). To construct DNA vaccines, the pathogen genome is sequenced and the genes for certain antigens are looked for.

These DNA sequences are then taken and placed into a plasmid (circular bacterial DNA), which results in a DNA vaccine encoding genetic information for one or several antigens. These DNA vaccines have been formulated into aerosols for pulmonary delivery in transgenic (human protein) mice.

This body of work has shown that the vaccine induced T-cell responses toward Mycobacterium tuberculosis sonicate antigen and that pulmonary administration had a significant advantage over intramuscular administration.

Currently, work is being done to look at how to stabilise these vaccines and how to create delivery systems for them. There is also particular interest in using viruses as delivery systems.

 

Reports from the 68th World Congress of Pharmacy and Pharmaceutical Sciences

Citation: The Pharmaceutical Journal URI: 10038135

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