044 - Cutaneous Reactions and Antibody Response to Intracutaneous Injections of Pneumococcus Polysaccharides

This study wasn’t as exciting as I expected, but I didn’t find that out until I was mostly finished with it, so I figured I’d go ahead with it and try to do better next time.

For vaccines against pneumonia caused by bacteria called pneumococcus, people tried whole bacterial cells, killed and injected, which worked somewhat, but wasn’t great. Then, over time, they realized they might not need to use whole cells, but only components of the cells’ capsule (see 028 and 039).

In today’s study, Maxwell Finland and Harry F. Dowling tested different kind of polysaccharides from pneumococcus capsules in volunteers with different histories of infection.¹

There were four groups of patients: 1) hospital patients with no recent infection, 2) hospital staff, 3) patients with recent pneumonia, and 4) patients with recent infections other than pneumonia (like typhoid or scarlet fever).

They tested types I, II, and III of pneumococcus polysaccharide, prepared in different ways, injected into the volunteers, and they tested the antibody responses by observing skin reactions and various other ways.

What they found, essentially, were the following: group 3 (recent pneumonia) showed immediate reactions to the skin test, specific to the strain with which they were infected. The different preparations of polysaccharide gave mostly similar results, except for those of type I pneumococcus. Sometimes, in the skin test, people in group 4 (who had some infection that wasn’t pneumonia) would show a delayed reaction to pneumococcal antigens while they had a fever, but after the fever passed, frequently they would no longer show a reaction.

But the most important (and interesting) finding of all was when they tested antibodies and reactions before and after immunization in volunteers that had not recently had pneumonia. The antibodies they found in blood samples before immunization were almost all low against all pneumococci, but after immunization with polysaccharides from specific types, the antibodies from the volunteers were almost all strong and specific to the type against which they were immunized.

How long the antibodies lasted depended on the type somewhat. Type I antibodies lasted the longest, at least eight weeks after injection; most seemed to peak around the second week. 

Later reviews and publications (including from the authors themselves) summarize this work well:

"Skin reactions were also elicited with varying frequency, using polysaccharides prepared by the same and by other methods, in normal subjects and in hospital subjects without pneumonia or recent intracutaneous injections. In such subjects, positive reactions to the initial injections were not correlated with the presence of circulating antibodies but the development of antibodies for the homologous pneumococcus type was stimulated by a single or by multiple intracutaneous injections.
     "[Finland and Dowling] found only minor differences in the antibody response elicited by the polysaccharides derived by different methods from the same type of pneumococcus. Delayed cutaneous reactions occurred only with the cellular carbohydrates."²

"Drs. Finland and Dowling also in the early 1930s, showed that the purified pneumococcal polysaccharide vaccine gave rise to type-specific antibodies."³

"Vaccines prepared from heat killed bacterial cultures were used for prophylactic inoculation in the early 1900s. However, due in part to poorly controlled clinical studies, their efficacy was questionable, which together with unacceptable reactogenicity meant this vaccination approach was not pursued. A new approach utilizing purified meningococcal polysaccharides was inspired by the successful use of pneumococcal polysaccharides to immunise humans."⁴

"Following on the heels of Avery and Heidelberger's revelations [that pneumococcal polysaccharides could be targeted by the immune system], Oscar Schiemann and Wolfgang Casper in Berlin demonstrated that purified pneumococcal capsular polysaccharides were immunogenic and engendered type-specific protection in mice. Finland et al. at Boston City Hospital's Thorndike Laboratory extended these findings through a series of experiments in the 1930s that paved the way for initial clinical trials of polysaccharide vaccines."⁵

 References:

1.  Finland, M. & Dowling, H. F. Cutaneous Reactions and Antibody Response to Intracutaneous Injections of Pneumococcus Polysaccharides. J. Immunol. 29, 285–299 (1935).

2.  Finland, M. & Brown, J. W. Reactions of Human Subjects to the Injection of Purified Type Specific Pneumococcus Polysaccharides. J. Clin. Invest. 17, 479–488 (1938).

3.  Krause, R. M. Prevention through Immunization: New Opportunities or End of the Road? J. Infect. Dis. 135, 318–329 (1977).

4.  Vipond, C., Care, R. & Feavers, I. M. History of meningococcal vaccines and their serological correlates of protection. Vaccine 30, Supplement 2, B10–B17 (2012).

5.  Artenstein, A. W. & LaForce, F. M. Critical episodes in the understanding and control of epidemic meningococcal meningitis. Vaccine 30, 4701–4707 (2012).