Anthrax vaccines: past, present and future.

[Guest guest]

I have not seen this old article posted to this list before, so here it is. I

will add to this subject shortly.

Gratitude expressed to a friend of mine who did the typing.

Anthrax vaccines: past, present and future.

C.B.Turnbull

Anthrax Section

Division of Biologics

Public Health Laboratory Service Centre,

Applied Microbiology and Research

Porton Down

Salisbury

Wiltshire

SP4 OJG

Vaccine, Vol, 9 August 1991

RESEARCH INTO NEW VACCINES

Overall satisfaction with the performance of the veterinary live spore

vaccine has meant that recently the predominant emphasis has been on

improving the human vaccines. In addition to the uncertain performance

outline above, the injection into human beings of crude and undefined

preparations is increasingly regarded as unsatisfactory, particularly, as in

the case of the Anthrax vaccines, when they are associated with frequent

complaints of unpleasant side-reactions.

It is for these reasons that, over the past few years, a significant amount

of work has gone into developing a second generation anthrax vaccine for

administration to humans which, as well as being fully defined (containing

only essential ingredients and producing effective levels of protection with

a single or, at worst, two doses), produces no side-reactions.

Anthrax having become a rare human disease in the west since the 1950s and

1960s, demand for the vaccines had become minimal and for a long period there

was little incentive to produce alternatives to those available. Ironically,

the incentive that arose was the supposed threat suggested by the belief of

western intelligence that a substantial human epidemic of anthrax in 1979 in

Severdlovsk, an industrial city in the Urals, was due to accidental escape of

B. anthracis from a military biological installation 24. The real extent and

cause of the outbreak in Severdlovsk remain unrevealed but the result was

that the 1980s were a decade of relative opulence for anthrax research, out

of which arose major new levels of understanding of the biochemical,

molecular and genetic basis of the disease and the host's defences against

it. As far as improved vaccines were concerned, the first of these advances

was the ability fully to purify and define the anthrax toxin components, PA,

LF and EF, which had first been separated and partially characterized in the

1950s and 1960s 25.26. The improved purifications 27-31 allowed the

development of enzyme immunoassays by which it became possible for the first

time to monitor the response to the vaccines in humans and guinea pigs to

protective immunity 14,15,20.22,23,32.

The second major advance with significant bearing on development of improved

vaccines was discovery 33-36 that the genes encoding the toxin lay on a large

plasmid subsequently designated pxo1and that curing B. anthracis of this

plasmid resulted in non-toxigenic avirulent derivatives.

During the course of vaccine-related studies in the 1980s, these two

developments-a sensitive and specific immunoassay for the toxin components

and the ability to produce non-toxigenic px01- strains of B. anthracis-led to

the clarification of a number of matters.

1. It was readily demonstrated that the toxin, or some part of it, was needed

in a vaccine for induction of protective immunity. Live non-toxigenic strains

conferred no protection while toxigenic non-capsulated (i.e.avirulent)

strains, e.g. the Sterne strain, induced good protection 22.

2. The belief, first formulated in 1963, that PA (then called factor ll) was

the main immunogen has been verified. PA in the absence of EF and LF has now

been shown to be capable of producing effective protection both as a purified

entity23,32,37 and when produced free of EF and LF in appropriately cloned B.

subtilis15,38. Consequently, protection has been noted in vaccinated animals

with high levels of anti-PA in the absence or near absence of anti-EF PA+ and

PA+EF combinations non-toxic (because LF and EF could no longer bind to the

PA) without altering the immunogenicity. A sterne-type strain of B. anthracis

in which the gene for PA carried the deletion could again be expected to be

entirely avirulent.

Summarizes the prototype vaccines for the immediate future. A combination of

PA with adjuvants 'DeTox' or 'Tri-Mix' (Ribi Immunochrm Research, USA)

perhaps shows most promise for human vaccine purposes among those within

these alternatives that have been subjected to protection tests. DeTox is a

mixture of monophosphoryl lipid A and cell wall skeleton from the BCG strain

of the tubercle bacillus; TriMix is DeTox+ trehalose dimycolate. As well as

being a chemically defined formulation lacking whole cell bacteria, it has

now been shown that considerably better protection can be induced with single

doses of the conventional UK or US vaccines (see Ref. 38, also Turnbull,

unpublished results). This vaccine is essentially ready for clinical trials

although a source of funding to cover this complex process 47 has not been

identified yet.