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Pneumococcal Vaccines

THE LANCET

IN pre-antibiotic days the pneumococcus wasfeared as a pathogen, an endemic cause of seriousillness and death. The search for specific means toprevent and treat pneumococcal pneumonia led, asearly as 1911, to field trials of an inactivated vac-cine among South African miners, but with onlypartial success.’ 1 Original, careful work laterrevealed that pneumococcal serotypes, each withan antigenically distinct polysaccharide capsule,were numerous, and that immunity was conferredby the corresponding type-specific serum anti-bodies. Antisera, raised in horses or rabbits, andcalibrated for potency against standard antisera,were found in laboratory animals and later in manto have therapeutic value in infections caused bythe same serotype. Specific treatment requiredidentification of the infecting serotype, which couldbe done rapidly on a sputum sample by means ofthe "quellung" or capsular reaction shown bypneumococci when exposed to type-specific anti-serum.2-6 Vaccine containing 30-60 p.g of polysac-charide capsular antigen from each of four impor-tant serotypes was shown to stimulate an antibodyresponse, to reduce the carrier rate of the same

serotypes, and to provide a useful measure of pro-tection in vulnerable groups such as recruits to theArmed Forces .7 ’ This successful work became allbut of academic interest when sulphonamides andthen the penicillins became freely available, but ithas lately been re-explored.The pneumococcus has not disappeared as a

dangerous pathogen. Fulminating cases of pneumo-coccal pneumonia with bacteraemia still occur,

being identified in the U.S.A. as a not uncommoncause of death;1,10 among hospital cases in NewYork in the 1950s the mortality-rate was 8% inyoung adults and as high as 30% in patients aged50 and over, despite the availability of antibiotics."Pneumococcal meningitis, though it is less common

1. Wright, E. A., Parry Morgan, W., Colebrook, L., Dodgson, R. W. Lancet,1914, i, 10, 87.

2. Neufeld, F. Z. Hyg. InfektKrankh. 1902, 40, 54.3. Neufeld, F., Händel, L. Arb. ReichsgesundhAmt. 1909, 34, 293.4. Dotchez, A. R., Avery, O. T. J. exp. Med. 1915, 21, 114. ibid. 1917, 26, 477.5 Heidelberger, M., Avery, O. T. ibid. 1923, 38, 73.6. Finland, M. J. Am. med. Ass. 1942, 120, 1294.7. Francis, T., Jr., Tillet, W. S. J. exp. Med. 1930, 52, 573.8. Macleod, C. M., Hodges, R. G., Heidelberger, M., Bernard, W. G. ibid.

1954, 82, 445.9. Austrian, R. in The Role of Immunological Factors in Infections, Allergic

and Autoimmune Processes (edited by R. F. Beers, Jr., and E. G. Bassett);p. 79. New York, 1976.

10. Sullivan, R. J., Jr., Dowdle, W. R., Marine, W. M., Heirholzer, J. C. Archsintern. Med. 1972, 129, 935.

11. Austrian, R., Gold, J. Ann. intern. Med. 1964, 60, 759.12. Goldacre, M. J. Lancet, 1976, i, 28.

than meningococcal and Hcemophilus influenzaemeningitis, is associated with a higher fatality-rate.12 The organism is also responsible for somecases of peritonitis in girls and, among other patho-gens, for otitis media, sinusitis, and infectious epi-sodes in patients with chronic bronchitis. Thepneumococcus is a particularly serious pathogen inpeople who are unusually susceptible to bacterial in-fections-for example, children with sickle-cell dis-ease-and it remains an important cause of respir-atory illness and death in diamond miners in SouthAfrica and isolated rural peoples in Papua NewGuinea. 13 Penicillin-resistant strains of Strepto-coccus pneumonia are also now being recog-nised,14-16 so far in small numbers except in PapuaNew Guinea, where penicillin has been widely usedin treatment of pneumonia; and also in South

Africa,IS,17 where a small hospital outbreak due toa resistant strain was described last year. 17 Thereare therefore good reasons for re-exploring the pos-sibilities of pneumococcal vaccines.The protective capsular antigen of pneumococci

can readily be extracted from cultures and purifiedto yield an almost chemically defined, stable pro-duct. The antigen should be very safe when used asa vaccine. It does not need to be detoxified, likediphtheria and tetanus toxins, and is not associatedwith other pharmacologically active molecules, asare other bacterial vaccines such as cholera, per-tussis, and typhoid. Polysaccharides often provehighly immunogenic when given in a single dose,possibly because unlike foreign proteins they arenot metabolised quickly, and a single injection of50-100 p.g seems to induce a satisfactory antibodyresponse in older children and adults. The exis-tence of at least 84 distinct serotypes of S. pneu-moniae has not proved the obstacle to vaccinationthat might have been expected. Although the dif-ferent serotypes occur as natural inhabitants of the

upper respiratory tract, most serious illnesses proveto be due to one of a smaller number of types, anda polyvalent vaccine derived from the fourteen orso commonest should immunise against about 80%of serious infections.9,18 A single injection of suchvaccines induces an antibody response to each com-ponent in most recipients. The distribution of sero-types varies in different parts of the world, but notgreatly-for example, types 2 and 25 are commonpathogens among South African miners but not inthe U.S.A. The types responsible for serious pneu-mococcal infection in the United Kingdom seem,

13. Riley, I. D., Tarr, P. I., Andrews, M., Pfeiffer, M., Howard, R., Challands,P., Jennison, G., Douglas, R. M. ibid. 1977, i, 1338.

14. British Medical Journal, 1971, ii, 667.15. Howes, J. V., Mitchell, R. G. Br. med. J. 1976, i, 996.16. Dixon, J. M. S., Lipinski, A. E., Graham, M. E. P. Can. med. Ass. J. 1977,

117, 1159.17. Appelbaum, P. C., Bhamjee, A., Scragg, J. N., Hallett, A. F., Bowen, A. J.,

Cooper, R. C. Lancet, 1977, ii, 995.18. Kaiser, A. B., Schaffner, W. J. Am. med. Ass. 1974, 230, 404.19. Amman, A. J., Addiego, J., Wara, D. W., Lubin, B., Smith, W. B., Mentzer,

W. C. New Engl. J. Med. 1977, 297, 897.

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from a survey in 1970 by the Public Health Labor-atory Service, to be similar to those in the U.S.A.The vaccine trials lately reported have been con-

ducted among people at high risk-diamondminers, children with sickle-cell disease, and pa-tients who have had their spleens removed.9,13,19Useful protection has been achieved at the cost ofonly minor side-effects (notably, sore arms). Theresults are certainly in favour of the cautious intro-duction and evaluation of these vaccines for protec-tion of high-risk groups. At present there has beenno serious consideration of use in normal childhoodimmunisation, which anyway might presentdifficulties: experience with meningococcal and

Haemophilus influenzae vaccines2O-22 suggests thatpolysaccharides can be poor antigens in babies.However, if continued use proves their safety andif antibiotic resistance becomes common, adminis-tration of pneumococcal vaccines to young childrencould become a possibility. Epidemiological studiesof the current importance of the pneumococcus asa pathogen would provide an essential background.

Limited Immunodeficiency

THE recurrent infections which arise in immuno-

deficiency are usually caused by many differentorganisms. But some immunodeficient individualsare susceptible to only a small range of pathogens,and the association between Haemophilus influenzceepiglottitis and certain MS blood-groupsl points toa genetic explanation. Antigen-specific defects ofthe immune response will be hard to characterisebecause of the limited extent of immunodeficiency.In mice the antibody response to certain singledefined antigens is determined by putative im-mune-response (Ir) genes2 but, in view of the numberof different antigens on most pathogens, an Ir genedefect is unlikely to cause immunodeficiency inman. Failure of the specific immune response is notnecessarily to blame for susceptibility to only a fewtypes of bacteria; for instance, individuals lackingthe sixth3 or eighth4 component of complement areespecially vulnerable only to neisserial infections.Other defects which might cause a limited immuno-deficiency are obscure so, for the present, an epony-mous title seems reasonable for what may turn outto be an antigen-specific defect affecting man. Dun-can’s disease, which is characterised by an unusualand commonly fatal outcome of infectiousmononucleosis (l.M), was originally recognised in 6

20. Goldschneider, I., Lepow, M. L., Gotschlik, E. C., Mauck, F. T., Bachl, F.,Randolph, M. J. infect. Dis. 1973, 128, 769.

21. Smith, D. H., Peter, G., Ingam, D. L., Harding, A. L., Anderson, P. Pedia-trics, 1973, 52, 637.

22. Gold, R., Lepow, M. L., Goldschneider, I., Gotschlik, E. C., J. infect. Dis.1977, 136, suppl. p. 531

1. Whisnant, J. K., Rogentine, G. N., Robbins, J. B. in Haemophilus Influenzae(edited by H. S. W. Sell and D. T. Karzon). Nashville, 1973.

2. Merryman, C., Maurer, P. H., Bailey, D. W. J. Immun. 1972, 108, 937.3. Leddy, J. P., et al. J. clin. Invest, 1974, 53, 544.4. Petersen, J. H., Graham, J. A., Brooks, G. F. ibid. 1976, 57, 283.

out of the 18 boys in the Duncan kindred .5 2 of the3 most severely affected boys had heterophile anti-bodies, transient hypergammaglobulinaemia, andatypical lymphocytes in the blood at the onset oftheir disease and they died within weeks. At nec-ropsy there was massive lymphoproliferationextending to the perivascular spaces in the cerebralcortex. In the other 3 boys the association withEpstein-Barr-virus infection (E.B.v., the aetiologicalagent of i.M.) was less certain and their- clinicalcourse lasted months or years. The heterogeneity ofthe clinical picture is apparent from other reports,6including a much larger family lately described byPURTILO and others.’ Of almost 70 male descen-dants of 3 presumed carrier sisters, 20 were

affected, on the evidence of fatal acute i.M.,acquired hypogammaglobulinaemia, American Bur-kitt’s lymphoma, plasmacytoma, or aplastic anae-mia. PuRTiLO et al. use the term "X linked reces-sive lymphoproliferative syndrome"; apart frombeing clumsy this is not always appropriate sincelymphoproliferation was absent from a quarter ofthose affected. The link with E.B.v. infection in themore recently described cases rests on the positiveheterophile-antibody tests and typical blood filmsof 2 fatal cases, on episodes of mononucleosis in atleast 2 others (one of whom died with an immuno-blastic sarcoma of B cells), and on the developmentof American Burkitt’s lymphoma in 2 familymembers. Conceivably other viruses were involvedin the remaining cases, but the immunopathologyof E.B.v. is so diverses that this "virus" might wellaccount for most features of the syndrome.

E.B.v. is transmitted largely by oral contact, andvirus has lately been detected in oropharyngealepithelial cells,9 so providing a direct explanationfor the pharyngitis of Lem. E.B.v. infects pre-dominantly B lymphocytes, and the abundance oflymphoid tissue close to the oropharyngeal mucosaprobably enables the virus to reach these cells. TheC3 receptor on the B-cell surface seems to be iden-tical to, or closely associated with, the receptor towhich the E.B.v. binds.10 In the first week of i.M. upto 1 in 2000 of blood lymphocytes carries the virus,as judged by the ability to infect other lymphocytesin tissue-culture." Over the ensuing weeks the pro-portion of infected lymphocytes falls, to reach con-trol levels (about 5 in 10’ cells) three months afterthe onset. A few virus-carrying cells are detected inmany healthy people who have had i.M. In thistendency to become latent, E.B.v. resembles otherherpesviruses, but the consequences may be dif-ferent, since some B cells which have incorporated

5. Purtilo, D. T. et al. Lancet, 1975, i, 935.6. Provisor, A. J., et al. New Engl. J. Med. 1975, 293, 62.7. Purtilo, D. T., et al. ibid. 1977, 297, 1077.8. Epstein, M. A., Achong, B. G. Lancet, 1977, ii, 1270.9. Lemon, S. M., et al. Nature, 1977, 268, 268.

10. Yefenof, E., Klein, G. Int. J. Cancer, 1977, 20, 347.11. Rocchi, G., De Felici, A., Ragona, G., Heinz, A. New Engl. J. Med. 1977,

296, 132.