O953 - Prophylactic immunization against measles, scarlet fever, diphtheria, whooping cough, and influenza

This paper was a speech given by Sir Ledingham, director of the Lister Institute in London. He says some interesting things. Speaking on the safety of vaccines:

"The safety of any method to be applied to man must always be a prime consideration. There must be no risk to life, and even the minor inconveniences, local and general, incidental to the introduction of a prophylactic through the skin must also, so far as possible, be reduced to a minimum consonant with the effectiveness of the product."

The first topic is diphtheria, a bacterial disease that can be prevented simply by inducing an immune response toward the toxin the bacteria produce (diphtheria toxin).

"Diphtheria undoubtedly merits chief consideration because we now know quite definitely from field trials...that intelligent and persistent immunization of the child population, starting with the pre-school child one year old, can bring the diphtheria morbidity down to zero."

The best approach to this is using something called toxoid, which is toxin treated such that it produces an immune response but doesn't cause problems.

"By the end of 1938 some 800,000 troops had been so vaccinated [with diphtheria toxoid], and Ramon was able to state that clinical diphtheria was disappearing from the French army."

"It is only when the proportion of vaccinated children reaches 70 to 80 per cent. that, as Ramon says, one sees the real fruits of one's work in a great reduction of the diphtheria incidence, perhaps to zero."

"Among the immunized children there have been since March, 1935, seventy-three notifications of diphtheria, giving an attack rate of 26 per 10,000 children, while among the unimmunized, including some 3,000 known Schick-negatives, the attack rate was 251 per 10,000, or ten times that among the immunized."

The Schick test was a way to test immunity in a person (though not perfect): if there was no reaction (Schick-negative), that indicated some immunity.

Considering the success of immunization, Ledingham makes a statement that seems relevant still today:

"When liberty becomes anti-social and impedes the application of scientific truth to the improvement of human well-being then I think some form of compulsion is the only remedy, though one might hope it would be merely temporary, pending the wider diffusion of scientific knowledge in the community."

It was a bit more complicated than just toxoid though, for diphtheria vaccine options. There was formol-toxoid, toxin-antitoxin floccules, alum-precipitated toxoid, and toxoid-antitoxin mixture, each with different properties in terms of safety or immune stimulation. Ledingham has some opinions:

"T.A.F. and T.A.M. are relatively innocuous at all ages, while A.P.T. is well borne in young children. In older children and adults it may give rise to painless nodes, which take some time to disappear. A.P.T., by virtue of the slowness of absorption of the antigen and consequent longer stimulus to the antibody-forming mechanism, can give rise...to considerably higher antitoxin titre, given in a single dose, than any of the other antigens. For this reason it may well become the antigen of choice for young children, the group we wish above all to see in course of time fully immunized"

In terms of stimulation, alum-precipitated toxoid seemed the best (probably the alum was an adjuvant); two doses of it was equivalent to three of formol-toxoid. Ledingham also stressed that trials of the vaccine should have prevention of diphtheria as their endpoint, not Schick test results; with a good vaccine, the test shouldn't be necessary. One dose with APT followed by another of FT might be good.

Then he moved on to whooping cough:

"As a killing disease of infancy, therefore, whooping-cough closely rivals diphtheria"

He cites Kendrick and Eldering's study that showed only 3.8% of vaccinated subjects with severe disease, compared to 13.1% in the unvaccinated, and other studies giving similar results.

"The age at which a pre-school child, say 9 months, may be submitted to immunization against diphtheria is also the age at which this same child might very desirably be immunized against whooping-cough. What is to be done? I am not aware that diphtheria toxoid has so far been administered in combination with a pertussis vaccine, but I see no reason why this should be attempted if Ramon's claim holds that the potency of diphtheria toxoid in mixture with T.A.B. [typhoid] vaccine is in now way interfered with and indeed appears to be enhanced. Such mixtures would first require to be tested on animals in which, at any rate, the rise in antitoxin titre can be accurately evaluated."

Then moving on to scarlet fever, he thinks it isn't worth trying to vaccinate most people, even if there were an effective vaccine, because it wasn't a serious disease anymore. Also it seemed that there was a patent preventing good vaccine development.

He thought treating measles with immune serum seemed to help, but there hadn't been much effort to acquire or store it. For active immunization, not enough was known yet about the disease.

With influenza though, more was known and a vaccine was closer, with some animal trials.

"One finding, however, which is likely to complicate the problem of active immunization as applied to man is the multiplicity of antigenic types among the strains recovered from different outbreaks of human influenza."

But he was frustrated by public health policy in general to some extent:

"When I reflect that, owing to ignorance, vested interest, or complacency in high places, a municipality is still prevented from ordering the pasteurization of all milk that comes into it, I sometimes despair of getting preventative science across."

One final quote:

"It may sound a totalitarian policy, if you like, but in essence it seems to me quite democratic, for it involves a negligible sacrifice on the part of the individual for his own and the common good."

Reference:

Ledingham, J. C. G. Prophylactic immunization against measles, scarlet fever, diphtheria, whooping cough, and influenza. British Medical Journal 2, 841–846 (1939).