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Email received 6th February 2010 from Dr Ruth Watkins (virologist and farmer)
Bovine Tuberculosis Vaccines. One of the most important considerations on how vaccines work is to know what immune factors protect against infection, and limit or clear infection.These are different when considering viruses and bacteria and protozoa and multicellular organisms.
In the case of viruses it is cytotoxic T-cells that clear virus infected cells (by asking them to commit suicide). Neutralising antibody (a few molecules of this special antibody when bound to the external surface of the virus inactivate the virus even if it subsequently enters a cell) has the role of preventing reinfection with the same serotype of virus, either upon recovery from infection or after successful vaccination. In the case of a highly effective vaccine as for instance against FMD the presence of neutralising anitbodies (made by B-cells) circulating in the blood and present in the saliva (from the secretion of saliva between the teeth) prevent infection (of cells) altogether upon exposure. There are of course some viruses that are not satisfactorily dealt with and cleared by the immune system and to which there is as yet no vaccine such as HIV the virus that causes AIDS.
In the case of bacteria, the animal host's defence is by phagocytosis and killing the bacterium in a phagosome, the sac in which the engulfed bacterium resides in the cell. The phagocyte cells are subsets of the white blood cells and are macrophages, dendrocytes, and so on found in blood and tissues (they are not T-cells nor B-cells). The majority of pathogenic bacteria do not wish to be inside a phagosome and are killed by the enzymes and free radicals they are exposed to in the phagosome. Antibodies to these bacteria are protective in that when they strongly bind with the surface of the bacterium they ensure it is engulfed by a phagocyte, thus it is doomed. Many pathogenic bacteria have mucilaginous capsules and upon first exposure to a meningococcus bacterium, for example type B which infects the throat initially, it may take 2 weeks to make antibody. If the bacterium invades, unluckily, before these antibodies have formed it is sufficiently slimey the phagocytes have difficulty engulfing it, and so pathogenic that it multiplies and causes disease (for example many types of bacteria which may invade us do not cause disease, are not pathogenic, and are unable to multiply because the host's iron binding protein binds iron more tightly than the bacterium's so the bacteria cannot grow as they has no access to iron).
However Mycobacterium tuberculosis and Mycobacterium bovis are among the bacteria that like to be in a phagosome. They survive there, and either remain latent and metabolically inactive or become metabolically active, grow and multiply. Their ability to grow very slowly and remain latent, inactive, are also special properties of these 2 mycobacteria. Whilst their existence in the immune system provokes a helper T-cell response and cytokine release such as gamma interferon (called a Th-1 response), a measurable antibody response early in infection is not usual (nor after subcutaneous inoculation of the BCG vaccine). M tuberculosis and M bovis are not killed in the phagosome unless there is a special stimulation of the of the cell that has engulfed them by gamma interferon, released by the Th-1 helper T-cells, to make the phagosome particularly toxic to the engulfed bacteria with very high levels of free radicals and so on.
Despite pathogenic bacteria having slimy mucilaginous capsules, or a waxy impermeable outer layer as in the case of mycobacteria, there are many molecules protruding which are proteins or complex molecules providing suitable antigenic sites for antibodies to bind should any specific antibodies be present.
Whilst antibody may be protective against some bacteria that give rise to extracellular infections such as staphylococcus, streptococcus and meningococci, it is not protective against infection with mycobacteria, it actually assists them to enter the very cells they would like to be in- at home in the phagosome.
The careful selection of the BCG bacterial strain, such as the Glaxo 1077 strain, has been shown to generate the Th-1 immune response, that is activated T helper cells that secrete gamma interferon and provoke the phagocyte that has engulfed a mycobacterium to kill it. In experimental infections in the laboratory in mice for example it is shown to be protective against infection and disease and death upon challenge. However this Th-1 response is subverted by infection with environmental mycobacteria such as avium species, so that the Th-1 is switched to Th-2 and the Th-2 ensures the production of (useless) antibody against mycobacteria as the Th-2 T helper cells interact with B-cells stimulating them to produce antibody, the T-cells in the Th-2 response do not produce gamma interferon to stimulate the phagocytes.
A high mycobacterial load in an infected animal has the same effect, switching off Th-1 and switching on Th-2. A Th-2 response is of no use to contain the infection, and will not give a positive skin test or bovigam test result either.
In humans it has been difficult to show the BCG vaccine is protective against infection, though there is some recent evidence of this apparently, but it certainly protects infants and young children against tuberculosis, widespread disease and death with a metaanalysis calculation of up to 83%. It has not proven so useful in pulmonary tuberculosis in adults. It is believed that the reasons the vaccine is of variable efficacy in different parts of the world and different people is the subversion of the protective immune response by environmental mycobacteria, see above in mice.
BCG is not effective if given after infection with M bovis or M tuberculosis.
Development of new vaccines have focussed on attempting to ensure the Th-1 or protective effect of BCG is sustained despite environmental mycobacteria exposure- this goal is not yet adequately achieved. Givng BCG to humans over the age of 35 for example is thought to be of no value- we cannot avoid environmental mycobacteria exposure during life.
(Later addition) Really, the organism is so complicated and interacts in such a subtle and manifold way with the host it does make anti-microbials seem a better bet than immunological manipulation of the host - I was quite surprised at Colin Fink's view of treating badgers but it has a lot to recommend it. Supposing isoniazid was effective at treating latency how much would it matter if an active infection became resistant? But then of course the 2nd generation of latent infections would not be treatable. So I think Dr Gillet is right.