Animal experiments have shown that respiratory administration of pertussis antigen induces a protective immune response. In this study pertussis antibody in human respiratory secretions was measured and the response to aerosol and intramuscular pertussis immunization investigated. Substantial increases in this antibody occurred after aerosol immunization but no changes were found in serum antibody. The reverse was observed after intramuscular immunization. Severe side effects are frequently seen after intramuscular pertussis vaccine in adults but not with aerosol immunization. The latter method may be of value for paediatric medical and nursing personnel exposed to the risk of pertussis infectio

Thomas, Gerald

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J. Hyg., Camb. (1975), 74, 233 2 3 3Printed in Great BritainRespiratory and humoral immune response to aerosoland intramuscular pertussis vaccineBY GERALD THOMASEssex Chemie AG, Topferstrasse 5, 6004 Lucerne, Switzerland(Received 4 October 1974)SUMMARYAnimal experiments have shown that respiratory administration of pertussisantigen induces a protective immune response. In this study pertussis antibodyin human respiratory secretions was measured and the response to aerosol andintramuscular pertussis immunization investigated. Substantial increases in thisantibody occurred after aerosol immunization but no changes were found in serumantibody. The reverse was observed after intramuscular immunization. Severeside effects are frequently seen after intramuscular pertussis vaccine in adults butnot with aerosol immunization. The latter method may be of value for paediatricmedical and nursing personnel exposed to the risk of pertussis infection.INTRODUCTIONDow (1940) showed that mice could be immunized by nasal instillation ofB. pertussis antigens against respiratory challenge with the homologous organism.North & Anderson (1942) suggested that the immunity obtained by this techniquewas both a general (circulating) specific immunity and a local respiratory immunityin which non-specific factors played a part. Cooper (1952) reported that intranasalinstillation of sublethal doses of live B. pertussis in mice appeared to induce ageneral and local immunity to challenge but pertussis vaccine given by this routeproduced only a local immunity to infection. Andersen (1952) suggested thatlarger doses of pertussis vaccine given intranasally would induce general as wellas local respiratory immunity.Immunoglobulins are known to be present in the respiratory secretions (Tomasi,Tan, Soloman & Prendergast, 1965) and are associated with specific antibodyactivity (Alford, Rossen, Butler & Kasel, 1967) which is contained almost entirelyin the IgA fraction. Most investigations into respiratory immunization have beenconducted with influenza vaccine and the results evaluated by epidemiologicalstudies, respiratory secretory antibody response and by live challenge procedures(Mann et al. 1968; Waldman, Mann & Kasel, 1968; Kasel et al. 1969; Thomas,1973). These studies have shown that specific protective antibodies can be inducedin respiratory tract secretions by local application of antigens. Holt (1972)restated the suggestions made by North & Anderson thirty years earlier regardingimmunity to whooping cough, i.e. there exists a general immunity (involvingpolymorphs and an opsonin) mobilized by the inflammatory response at the surfacehttps:/www.cambridge.org/core/terms. https://doi.org/10.1017/S0022172400024293Downloaded from https:/www.cambridge.org/core. University of Basel Library, on 11 Jul 2017 at 08:18:08, subject to the Cambridge Core terms of use, available at234 GERALD THOMASof the respiratory mucous membrane and a local prophylactic immunity involvingspecific secretory IgA antibodies.The investigations described in this paper are concerned with the variations inantibody concentrations in respiratory secretions after aerosol and intramuscularimmunization with B. pertussis vaccine. Holt (1972) attempted to detect antibodyto B. pertussis in respiratory secretions and sera from an aerosol-immunizedTaiwan monkey, using a tissue culture adsorption-inhibition technique, andobtained very variable results. In the investigations described in this paper aradio-immunoassay technique was used to estimate antibody titre to B. pertussisin respiratory secretions.MATERIALS AND METHODSVaccinesThe intramuscular pertussis vaccine contained 4 x 1010 organisms/ml. (BurroughsWellcome & Co., London). Respiratory pertussis vaccine was prepared by freeze-drying the intramuscular vaccine and was administered by means of a metereddose pressurized aerosol container (3 Ms Laboratories, Loughborough, England).Respiratory secretions and seraRespiratory secretions were obtained from eight human volunteers and examinedfor protein and IgA content as previously described (Thomas, 1973). Antibodytitres in respiratory secretions were examined by passive haemagglutination(Cruickshank, Duguid & Swain, 1965) and a radio-immunoassy technique (Restall,Thomas & Pennant, 1973) adapted from the method described by Rosenthal,Hayashi & Notkins (1972). Since the IgA content of the nasal secretion samples(and hence the antibody concentrations) varied considerably from one sample toanother a standardization procedure was adopted to make the samples comparable.mu r ii • r 1 J counts/second x 100The following formula was used —; . Antibody titres in sera were& IgA content Jassayed by the passive haemagglutination method, using the vaccine strain ofB. pertussis to coat the sensitized sheep cells.Immunization and sampling proceduresSix adult volunteers received 3 doses of 0-5 ml. of vaccine intramuscularly atmonthly intervals. Serum and respiratory secretion samples were obtained beforeimmunization and 3 weeks after the last dose of vaccine. Eight adult volunteersreceived one dose of aerosol vaccine inhaled via the nostrils (equivalent to 0-5 ml.of the vaccine given intramuscularly). Serum and respiratory secretion sampleswere obtained before immunization and 3 weeks after immunization.RESULTSPassive haemagglutinationAntibody was not detectable in any of the respiratory secretion samples by thismethod (nor by slide or tube agglutination) from the two groups of volunteers.https:/www.cambridge.org/core/terms. https://doi.org/10.1017/S0022172400024293Downloaded from https:/www.cambridge.org/core. University of Basel Library, on 11 Jul 2017 at 08:18:08, subject to the Cambridge Core terms of use, available atAerosol pertussis vaccine 235Table 1. Serum antibody titres for Bordetella pertussis by passive haemagglutinationmethod, in aerosol immunized and intramuscularly immunized volunteersAerosol immunization Intramuscular immunizationVolun-teerno.12345678ReciprocalserumBeforeimmuniz-ation48448244i titresAAfterimmuniz-ation48428448Volun-teerno .91011121314Reciprocalserum titresAc \Before Afterimmuniz- immunization ation2 168 328 1284 328 164 32Table 2. Radio-immunoassay of antibody to Bordetella pertussis in respiratorysecretions from aerosol immunized and intramuscularly immunized volunteersBefore immunization After immunizationVolunteerno.1 aer*23456789i.m.f1011121314IgA(/ig./ml.)59-350-571-339-725-028-014-118-21 1 011-03 9 049-01 2 027-0c/s3382651122252369611714535837801702591c/sx 100IgA5705251575679443438307973187542000346208337IgA(/tg./ml.)28-028-011-715-520-78-830-020-720-715-511-731-544-220-7c/s3072135520826687258280c/s x 100I g A1096760470134212859898601353Difference+ 526+ 235+ 313+ 775+ 341+ 646+ 30+ 556Average difference + 42874134259968469Ave3578642214305190333+ 39+ 110+ 214- 4 1- 1 8- 4;rage difference + 50* Aer = aerosol immunized. f i-m- = intramuscularly immunized,c/s = counts/second.Serum antibody to B. pertussis (Table 1) was present in all the samples from bothgroups. No significant changes were seen in the aerosol post-immunization serumtitres while five of the six intramuscular post-immunization titres showed four-fold or greater increases.https:/www.cambridge.org/core/terms. https://doi.org/10.1017/S0022172400024293Downloaded from https:/www.cambridge.org/core. University of Basel Library, on 11 Jul 2017 at 08:18:08, subject to the Cambridge Core terms of use, available at236 GERALD THOMASRadio-immunoassayB. pertussis antibody was present in all the respiratory secretion samples fromboth groups (Table 2). Significant changes were evident only in the aerosol post-immunization samples.DISCUSSIONSerum antibody titres to B. pertussis are frequently relatively low in adults(Kendrick et al. 1969; Abbott, Preston & Mackay, 1971). Even after several intra-muscular injections antibody titres do not rise remarkably (Abbott et al. 1971).The titres for the intramuscularly immunized volunteers (Table 1) are similar tothose described by other workers. It is thus not surprising that increases in serumantibody titres were not recorded after aerosol immunization with only a thirdof the quantity of antigen given to the intramuscularly immunized group.Detection of antibody to B. pertussis in respiratory secretions required thesensitivity of the radio-immunoassay technique. The results in Table 2 show areversal of the situation compared with serum antibody. Substantial increases inantibody titre were observed in all of the samples from the aerosol-immunizedvolunteers, while the intramuscularly immunized group showed only small in-creases in titre in half of the samples. The numbers involved however are small andsimilar investigations in larger groups are obviously desirable to verify theseobservations.Holt (1972) suggested that the antibody present in respiratory secretions actsby inhibiting adhesion of the organism to the cilia of the mucous membrane whilethe serum antibody has a bactericidal effect exerted when inflammatory changesin the mucous membrane permit transudation of serum proteins. Under thesecircumstances aerosol immunization (with the dose of antigen given in thisinvestigation) appears to induce only the prophylactic protective mechanism sinceserum antibody concentrations were unchanged. Larger doses, up to the level ofthe intramuscular regimen, may however influence serum antibody.Aerosol immunization against whooping cough cannot at this stage be recom-mended for use in infants but it may have a place in the protection of adults,especially those exposed to infection such as doctors and nursing staff concernedwith paediatric infectious diseases. Outbreaks of whooping cough in adults areknown to occur (Editorial, 1968). Intramuscular immunization of adults is oftenassociated with severe side effects (as was observed during the course of thisinvestigation). Aerosol administration of the B. pertussis antigens was not ac-companied by any side effects in the eight volunteers (nor by the author whoreceived four doses by this route). For adults aerosol immunization would bea much preferred method of protection.I wish to thank Mr S. W. F. Restall and Mr J. H. Pennant for technical assist-ance with these investigations and 3 Ms Laboratories, Loughborough, Englandfor their assistance in preparing the B. pertussis aerosol vaccine.https:/www.cambridge.org/core/terms. https://doi.org/10.1017/S0022172400024293Downloaded from https:/www.cambridge.org/core. University of Basel Library, on 11 Jul 2017 at 08:18:08, subject to the Cambridge Core terms of use, available atAerosol pertussis vaccine 237REFERENCESABBOTT, J. A., PRESTON, N. W. & MACKAY, R. I. (1971). Agglutinin response to pertussisvaccination in the child. British Medical Journal i, 86.ANDERSEN, E. K. (1952). Some observations made during experiments on mice inoculatedwith H. pertussis. Acta pathologica et microbiologica seandinavica 32, 125.ALFORD, R. N., ROSSEN, R. D., BUTLER, W. T. & KASEL, J. A. (1967). Neutralizing andhaemagglutination inhibiting activity of nasal secretions following experimental humaninfection with A2 influenza virus. Journal of Immunology 98, 724.COOPER, G. N. (1952). Active immunity in mice following the intranasal injection of sub-lethaldoses of living Haemophilus pertussis. Journal of Pathology and Bacteriology 64, 65.CRUICKSHANK, R., DUGUID, J. D. & SWAIN, R. H. A. (1965). Medical Microbiology. London:E. & S. Livingstone Ltd.Dow, R. P. (1940). Active immunisation by the intranasal route. Canadian Journal of PublicHealth 31, 370.EDITORIAL (1968). Pertussis in adults. Annals of Internal Medicine 68, 593.HOLT, L. B. (1972). The pathology and immunology of Bordetella pertussis infection. Journalof Medical Microbiology 5, 407.KASEL, J. A., HUME, E. B., FULK, R. V., TOGO, Y., H U B E B , M. & HORNICK, R. B. (1969).Antibody response in nasal secretions and serum of elderly persons following local orparenteral administration of inactivated influenza virus. Journal of Immunology 102, 555.KENDRICK, P. L., GOTTSHALL, R. Y. M., ANDERSON, H. D., VOLK, V. K., BUNNEY, W. E. &FRANKLIN, H. T. (1969). Pertussis agglutinins in adults. Public Health Reports, Washington84, 9.MANN, J. J., WALDMAN, R. H., TOGO, Y., HEINER, G. G., DAWKINS, A. T. & KASEL, J. A.(1968). Antibody responses in respiratory secretions of volunteers given live and deadinfluenza virus. Journal of Immunology 100, 726.NORTH, E. A. & ANDERSON, G. (1942). Active immunisation by the intranasal route in experi-mental pertussis. Medical Journal of Australia ii, 228.RESTALL, S. W. F., THOMAS, G. & PENNANT, J. H. (1973). A radio-immuno-assay techniquefor the titration of bacterial antisera. M.R.E. Report No. 75. Microbiological ResearchEstablishment, Porton, Salisbury, Wilts, England.ROSENTHAL, J. D., HAYASHI, K. & NOTKINS, A. L. (1972). Rapid microimmunoassay for themeasurement of antiviral antibody. Journal of Immunology 109, 171.THOMAS, G. (1973). Respiratory immunization with inactivated influenza aerosol vaccine inman followed by live challenge. Airborne transmission and airborne infection. IVth Inter-national Symposium on Aerobiology. Utrecht: Oosthek Publishing Co.TOMASI, T. B., TAN, E. M., SOLOMAN, A. & PRENDERGAST, R. A. (1965). Characteristics ofan immune system common to certain external secretions. Journal of ExperimentalMedicine 121, 101.WALDMAN, R. H., MANN, J. J . & KASEL, J . A. (1968). Influenza virus neutralizing antibodyin human respiratory secretions. Journal of Immunology 100, 80.https:/www.cambridge.org/core/terms. https://doi.org/10.1017/S0022172400024293Downloaded from https:/www.cambridge.org/core. University of Basel Library, on 11 Jul 2017 at 08:18:08, subject to the Cambridge Core terms of use, available at

Respiratory and humoral immune response to aerosol and intramuscular pertussis vaccine

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