Impaired serum antibody response to inactivated influenza A and B vaccine in cancer patients H. GRANT STIVER, MD; BRIAN H. WEINERMAN, MD
Vaccination against influenza has been advocated for certain persons who are at high risk of pneumonic complications of influenza. This group includes the elderly and persons with chronic cardiovascular disease, pulmonary disease, renal disease or diabetes.1 Arguments that influenza vaccine should also be given to cancer patients are based on the facts that undue mortality in this group occurs during influenza epidemics,1'2 and that influenza may cause interruption of cancer therapy for up to several weeks.3 Clearly the titre of serum hemagglutination-inhibiting (HI) antibody correlates with the degree of protection from disease.4'5 Knowledge of the antibody response would therefore be necessary before programs are instituted for administering vaccine to cancer La reponse s6rologique a Ia vaccination avec un vaccin influenza inactive et patients since many of them are rebivalent contenant les antigenes ceiving immunosuppressive drugs, are A/Port Chalmers/I /73 (H3N2) et ill from active disease or may be hyB/Hong Kong/5/72 a et6 mesur6e chez pogammaglobulinemic as a conse44 patients cancereux et chez 27 sujets quence of their disease. Any of these temoins sains. Une augmentation du factors may affect the individual's titre d'anticorps de quatre fois ou plus immune response to vaccination. aprAs Ia vaccination est survenue This study was undertaken to aschez 16 des 44 patients cancereux et sess the serum antibody response to chez 25 des 27 temoins pour l'antigAne A, et chez 14 des 44 patients cancereux influenza A and B vaccine in a group of patients with various malignant et chez 20 des 27 temoins pour l'antig&ne B. Les patients souffrant de diseases in comparison with that in lymphome, qui avalent tendance A healthy vaccinated controls, and to faire de l'hypogamaglobulin6mie, ont determine the relation of the antir6pondu moms bien que les patients body response to chemotherapy, type ayant des tumeurs solides. Chez ces of disease and prognosis.
The serum antibody response to vaccination with bivalent inactivated influenza vaccine containing A/Port Chalmers/I /73 (H3N2) and B/Hong Kong/5/72 antigens was assessed in 44 patIents with cancer and in 27 healthy control subjects. A fourfold or greater increase in antibody titre after vaccination occurred in 16 of the 44 cancer patients and 25 of the 27 controls for the A antigen, and in 14 of the 44 cancer patients and 20 of the 27 controls for the B antigen. Patients with lymphoma, who tended to have hypogammaglobulinemia, responded less well than did patients with solid tumours. Among the latter the failure to show a fourfold or greater increase in antibody titre correlated with a poorer 18-month survival.
derniers l'echec de faire augmenter par quatre fois ou plus le titre d'anticorps 6tait associ6 A une moms bonne survie A 18 mois.
From the departments of medicine and medical microbiology, University of Manitoba, and the sections of infectious diseases and of oncology and hematology, St. Boniface General Hospital, Winnipeg Presented in part at the 17th Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, Oct. 12 to 14, 1977 Reprint requests to: Dr. H. Grant Stiver, Section of infectious diseases, Department of medicine, St. Boniface Hospital, Winnipeg, Man. R2H 2A6
Methods
oral administration of cyclophosphamide, 100 mg/in2, for 14 days starting on day 1. Prevaccination influenza antibody titres were determined on day 1 and the first postvaccination titres 2 to 3 weeks after cyclophosphamide therapy was discontinued (days 28 to 35) and before any further chemotherapy was given. Of the patients 19 had lymphomas, 4 had chronic lymphocytic leukemia, 3 had multiple myeloma, 1 had Waldenstr6m's macroglobulinemia and 1 had polycythemia vera. Of the 19 patients with lymphomas 7 had diffuse well differentiated lymphocytic lymphoma, 6 had nodular poorly differentiated lymphocytic lymphoma, 2 had diffuse poorly differentiated lymphocytic lymphoma, 2 had diffuse histiocytic lymphoma, 1 had diffuse mixed lymphocytic lymphoma, and 1 had nodular sclerosing Hodgkin's disease. Of the 19, 2 had not had chemotherapy for at least 4 weeks at the time of vaccination, 6 were receiving chlorambucil therapy daily and 5 were receiving cyclophosphamide, 400 mg/in2, orally for 5 days. The postvaccination titre was determined more than 2 weeks after the last dose of cyclophosphamide was given. The remaining six patients were receiving 600 mg/in2 of cyclophosphamide and 2 mg of vincristine on days 1 and 8 of a 14-day course of prednisone and procarbazine. The four patients with chronic lymphocytic leukemia were receiving chlorambucil daily at the time of vaccination. The ages of the patients ranged from 32 to 79 years (mean 59 years). Gamma globulin concentrations were noted on the charts of 27 of the patients. In all 44 patients the disease was staged according to standard criteria. The total dose of chemotherapeutic agents and the date of the last dose in relation to that of vaccination were recorded. The second group of vaccinated persons was composed of 27 healthy hospital employees ranging in age from 20 to 49 years (mean 26 years).
Patient population The patient population consisted of two groups. The first was a group of 44 patients with malignant disease being cared for by the section of oncology and hematology, department of medicine, St. Boniface General Hospital, Winnipeg. Of 16 patients who had solid tumours, 13 had metastatic breast carcinoma; all 13 underwent treatment with cyclophosphamide, methotrexate and 5-fluorouracil, which consisted of injections of 5-fluorouracil and methotrexate on days 1 and 8 and CMA JOURNAL/OCTOBER 7, 1978/VOL. 119 733
No member of either group had received influenza vaccine during the previous 2 years. Vaccination procedure In October, November and December 1975 each member of both groups was given a single intramuscular injection of commercially available bivalent aqueous whole-virus influenza vaccine (Fluax, Merck Sharp & Dobme Canada Limited) containing 700 chicken cell agglutinating units of A/Port Chalmers! 1 / 73 (H3N2) and 500 chicken cell agglutinating units of B/Hong Kong! 5/72 antigen. Blood samples for serologic testing were drawn prior to vaccination and again from 2 to 8 weeks afterwards. Measurement of antibody response Samples of serum from patients and controls were paired for simultaneous analysis. By means of the HI test6 with chicken erythrocytes on microtitre plates the samples were tested against the homologous virus strains A/Port Chalmers/ 1 / 73 (H3N2) and B/Hong Kong/5/72, provided by the Laboratory Centre for Disease Control, Ottawa. All serum pairs were inactivated at 560C and treated with receptor-destroying enzyme according to standard procedures.6 Statistical analysis was performed by means of the chi-square test.
in 14 of the 44 cancer patients compared with 20 of the 27 controls (P < 0.001). The geometric mean increase in titre was 2.9 for the cancer patients compared with 8.2 for the controls. Static titres were noted in 24 cancer patients and in 2 controls. The seroconversion rates for patients with different types of malignant disease indicated that the group with lymphomas had a less favourable response than the group with solid tumours to the A/ Port Chalmers antigen. A fourfold or greater increase in antibody titre occurred in only 4 of the 19 patients with lymphomas as opposed to 8 of the 16 patients with solid tumours (P < 0.02). A fourfold increase did not occur in any patient with chronic lymphocytic leukemia, but three of the four patients with malignant monoclonal gammopathies who were receiving chemotherapy did respond.
CONTROL GROUP (n27)
CANCER PATIENTS (n44)
z 0
4
z C., C., 4 I(/)
0 0. w I-
z
Results The numbers of cancer patients and controls who were seronegative (titre of 8 or less) before vaccination were not significantly different (34 of 44 patients and 17 of 27 controls for the A strain, and 39 of 44 and 22 of 27 for the B strain). The serum antibody response to the A/Port Chalmers/i / 73 (H3N2) antigen is illustrated in Fig. 1. A fourfold or greater increase in titre occurred in 16 of the 44 patients with cancer compared with 25 of the 27 controls (P < 0.001). The geometric mean increase in titre was 3.0 for the cancer patients compared with 27.4 for the controls. Static titres were observed in 26 cancer patients but in only 1 control. Similar differences in response to the B/Hong Kong/5/72 antigen were observed (Fig. 2). A fourfold or greater increase in titre occurred
Inexplicably there was no significant difference in response rates to the B antigen between the patients with lymphoma and those with a solid tumour. When survival rates at 18 months after vaccination were analysed there appeared to be some correlation between a fourfold or greater increase in antibody titre and survival, but only in the group with solid tumours. Ten of 12 patients with a fourfold or greater increase in antibody titre in response to either the A or the B antigen were alive at 18 months compared with 3 of 8 patients who did not respond to either antigen. There were no factors other than hypogammaglobulinemia that correlated with failure to respond to vaccination. A low gamma globulin concentration in response to A/Port Chalmers antigen was found in 10 of 18 patients with less than a four-
8
16
32
64
128
256
512 1024
8
HI TITRE PREVACCINATION
16
32
64
128 256
512 1024
HI TITRE PREVACCINATION
FIG. 1-Serum hemagglutination-inhibiting (HI) antibody response to A/Port Chalmers/1/73 (H3N2) antigen. Bottom diagonal line represents no rise in litre, dotted line represents twofold rise, upper line represents fourfold rise. CANCER PATIENTS (n=44)
CONTROL GROUP (n27) S
S
z
0 4
z C.) C.)
4
IC,,
0 0. w
z 8
16
32
64
128
256
512 1024
8
16
32
64
128
256
512 1024
HI TITRE PREVACCINATION
Kong/5/72 antigen. Interpreta-
fold increase in antibody titre, all of whom had lymphoma or chronic lymphocytic leukemia, but in none of 9 patients with a fourfold or greater increase. The mean ages (57.2 and 60.2 years), proportions seronegative before vaccination (81.2% and 75.0%), absolute lymphocyte counts (1.130 and 0.950 x 10'/L) and degrees of fall in the count after chemotherapy, and total cyclophosphamide dose up to the time of vaccination (5150 and 7516 mg) were not significantly different in responders and nonresponders. Although each of the two patients who received remote chemotherapy responded to one antigen, the seven patients with solid tumours who responded to both antigens had received a slightly higher dose of chemotherapeutic agents at the time of vaccination than had the eight patients with such tumours who did not respond to either antigen. Nor was there any difference in seroconversion rates related to whether serum was drawn less than or more than 3 weeks after vaccination. Of the patients with a fourfold or greater increase in antibody titre in response to the A and B antigens 44% and 30% respectively had blood samples drawn less than 3 weeks after vaccination, whereas of those with an increase in titre less than fourfold 30% and 42% respectively had blood samples drawn more than 3 weeks after vaccination. Discussion Several studies in patients with solid neoplasms have shown good correlation between initial cell-mediated immune responsiveness and the subsequent clinical course.. With regard to humoral response, Heath, Fairley and Malpas' demonstrated that the antibody response to Swine, WS, A/England/S 1, A/Singapore! 57 and B/England/59 influenza antigens was poorer than normal in patients with reticuloses, normal in those with acute leukemia, and low in those with multiple myeloma or chronic lymphocytic leukemia. Although local secretory antibodies and other types of humoral antibody such as antineuraminidase and neutralizing antibody, as well as cell-mediated immunity, all play an important role in host defence against influenza, most studies have used serum HI
antibody as an index of the protec- another, where tetanus toxoid was tion afforded by vaccine. Comple- used, it was impaired.'3 In our study ment-fixation antibodies against the the antibody response in patients with nucleoprotein antigen of the influen- solid tumours was impaired in comza virus do not correlate with the parison with that in healthy persons, and within the group with solid tuprotection conferred. The results of our study agree with mours a poor response correlated those of Feery and colleagues,' who with a poorer 18-month survival. found a suboptimal HI antibody re- Lower survival rates in patients with sponse to A/Port Chalmers vaccine solid malignant tumours have been in patients with lymphoma and leuke- found to correlate with poor antibody mia. These authors reported that, response to tetanus toxoid." Other despite a generally retarded response workers have found significantly dein these patients compared with creased rates of antibody response healthy subjects, 83% and 57% of to influenza vaccine in immunosupthe patients achieved satisfactory pressed patients with renal transtitres of antibody to A/Port Chal- plants, but again no correlation with mers and B/Hong Kong vaccine re- the dose of immunosuppressive drugs spectively. However, prevaccination was discovered.'4 Although age may geometric mean titres were already affect the degree of response to in20 or higher in 70% of patients to fluenza vaccine'5 (admittedly our Port Chalmers and in 40% to control group was younger than the B/Hong Kong. In our study, as cancer group) some studies have not shown in Figs. 1 and 2, only 22% been able to correlate diminished reand 11 % of patients had HI titres sponsiveness to tetanus toxoid'2 or equal to or greater than 16 before influenza vaccine'6 with age. vaccination. In the remainder, the The reasons for failure of cancer "seronegative" group, only 21 % and patients to respond to inactivated in36% had probably protective'0 post- fluenza vaccine are unclear. Despite vaccination titres of 16 or greater to the lack of correlation of poor antiA/Port Chalmers and B/Hong Kong body response with dose or type of chemotherapeutic agent, these drugs respectively. In a recent study of the mass vac- probably do play an important role. cination program against swine in- Further studies of the mechanisms fluenza in the United States, an im- of action of vaccine are required, paired antibody response to A/New perhaps with analysis of the function Jersey/ 76 antigen was demonstrated of thymus (T)- and bursa (B)-derived in patients with lymphoreticular and lymphocytes, to help define the host's solid neoplasms." In contrast to our response to these antigens. The relaresults, no difference was found be- tion we found between survival and tween the groups with lymphoreti- a fourfold increase in antibody titre cular and solid tumours in that study in the group with solid tumours sugas to the proportions with a fourfold gests that inability to control tumour increase in antibody titre. A better growth and spread is linked with inseroconversion rate was observed in ability to mount a humoral antibody patients who had pre-existing anti- response, which in turn may be asbody, and when patients received sociated with a defect in the recognivaccine between courses of chemo- tion of antigens by T-lymphocytes. therapy the antibody response was Perhaps a higher degree of immunity not significantly different from that would be conferred by live attenuated of controls. Just as we did, these in- vaccines, but these might cause disvestigators found a significantly de- ease in immunosuppressed hosts. In creased antibody response if vaccine one study a second dose of influenza was given at the time of chemother- vaccine administered 2 weeks after apy but, similarly, no correlation was the first resulted in a fourfold infound between the response and the crease in antibody titre in four of dose of chemotherapeutic drugs or seven patients who had not responded to a single dose.' Adjuvants per se, the absolute lymphocyte count. Additional studies have examined such as bacille Calmette-Gu.rin, the antibody response to other anti- have been shown to heighten protecgens in patients with solid tumours. tion from influenza virus challenge In one of these the antibody response in animals, either by accelerating proto yellow fever vaccine was equal to duction of humoral antibodies or by that in healthy subjects,'2 while in stimulating cell-mediated immunity.'7 CMA JOURNAL/OCTOBER 7, 1978/VOL. 119 735
Nc1.UL (amoxicillin) AMOXIL. (amoxicillin)... A new generation broad-spectrum penicillin. INDICATIONS: Infections due to susceptible strains of the following microorganisms: Gram-negative-H. influenzae, E. coil, R mirabilis and N.gonorrhoeae. Gram-positive-Streptococci, D.pneumoniae and penicillin-sensitive staphylococci. In emergency cases where the causative organism is not yet identified, therapy may be initiated with AMOXIL on the basis of clinical judg ment while awaiting the results of bacteriologic studies. DOSAGE AND ADMINISTRATION: Infections of the ear, nose and throat due to streptococci, pneumococcl, and penicillin-sensitive staphylococci; infections *of the upper respiratory tract due to H. influenzae; in fections of the genitourinary tract due to E. coli, R mirabilis, and S. faecalis; infections of the skin and soft tissues due to streptococci, genicillin-sensitive staphyioc.occi and E. coli: sual Dese: Adults-250 mg every 8 hours. Children-25 mg/kg/day in divided doses every 8 hours. This dosage should not exceed the recommended adult dosage. In severe infections or infections caused by less sensitive organisms: 500 mg every 8 hours for adults, and 50 mg/k9/day in divided doses every 8 hours for children. Infections of the lower respiratory tract due to streptococci, pneumococci, penicillin-sensitive staphylococci and H. influenzae: Usual Dese: Adults-500 mg every 8 hours. Children-50 mg/kg/day in divided doses every 8 hours. This dosage should not exceed the recommended adult dosage. Urethritis due to N. gonorrhoeae: 3 g as a single oral dose. Patients with Qonorrhea, with a suspected lesion of syphilis, should have darkfieid examinations before receiving AMOXIL, and monthly serologic tests for a minimum of four months. For chronic urinary tract infections, frequent bacteriologic and clinical appraisals are necessary. Smaller doses than those recommended above should net be used. Stubborn infections may require several weeks' treatment, sometimes at higher doses than recommended above. Concurrent bacteriolo8 ic sensitivity monitoring is recommended. ontinued clinical and/or bacteriologic follow-up for several months after cessation of therapy may be required. Treatment should continue for 48 to 72 hours beyond the time patient becomes asymptomatic or bacterial eradication is obtained. At least 10 days' treatment is recommended for infections caused by beta-hemolytic streptococci to prevent acute rheumatic fever or glomerulonephritis. CONTRAINDICATION: In patients with a history of allergy to the penicillins or the cephalosporins. PRECAUTIONS: Periodic assessment of renal, hepatic, and hematopoletic function should be made during prolonged AMOXIL therapy. AMOXIL is excreted mostly by the kidney. The dosage administered to patients with renal impairment should be reduced proportionately to the degree of loss of renal function. The possibility of superinfections with mycotic or bacterial organisms should be kept in mind during therapy. If superinfections occur (usually involving Aero bacter, Pseudomonas or Candida), the drug should be discontinued and aproriatetherapy instituted. ADVERSE REACIONS. As with other penicillins, presumably the most common untoward reactions will be related to sensitivity phenomena, similar to those observed with ampicillin. They are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and in those with a history of allergy, asthma, hay fever or urticaria. (See Product Monograph which is available on request).SUPPLI ED: AMOXIL-250 Capsules (250 mg amoxicillin) in bottles of 100 and 500. AMOXIL-500 Capsules (500 mg amoxicillin) in bottles of 100. AMOXIL-125 Suspension(125 mg amoxicillin per 5 ml) in bottles of 75, 100 and 150 ml. AMOXIL-250 Suspension (250 mg amoxicillin per S ml) in bottles of 75, 100 and 150 ml. AMOXIL Pediatric Drops (50 mg amoxicillin per ml) in bottles of 15 ml. AYERST LABORATORIES Division of Ayerst, McKenna & Harrison Limited Montreal, Canada Made In Canada by arrangement with Reg'd BEECHAM INC.
Administration of these agents should be studied in conjunction with influenza vaccination as a possible means of augmenting the humoral antibody response in patients with cancer. We are grateful to James Kennedy for technical assistance and to Janice Coulter for preparation of the manuscript. This work was supported by a grant from the St. Boniface General Hospital Research Foundation.
References 1. EICKHOFF TC, SHERMAN IL, SERFLING
RE: Observations on excess mortality associated with epidemic influenza.
JAMA 176: 776, 1961 2. HouswoRris J, LANGMUIR AD: Excess mortality from epidemic influenza, 1957-1966. Am J Epidemiol 100: 40, 1974 3. FELDMAN 5, WEBSTER RG, SUOG M: Influenza in children and young adults with cancer - 20 cases. Cancer 39: 350, 1977 4. HonsoN D, CURRY RL, BEARE AS, et
antibodies by cancer patients. Clin Exp immunol 7: 839, 1970 13. LYrrON B, HUGHES LE, FULTHORPE AJ: Circulating antibody response in malignant disease. Lancet 1: 69, 1964 14. Snvm. HG, GRAVES P, MEIKLEJOHN G, et al: Impaired serum antibody response to inactivated influenza A and B vaccine in renal transplant recipients. Infect Immun 16: 738, 1977 15. HOWELLS CHL, VESSELINOVA-JENKINS CK, EVANS AD, et al: Influenza vaccination and mortality from bronchopneumonia in the elderly. Lancet 1: 381, 1975 16. FEERY BJ, EVERED MG, MORRISON El: Antibody responses to influenza virus subunit vaccine in the aged. Med J Aust 1: 540, 1976 17. SPENCER JC, GANGULY R, WALDMAN
RH: Nonspecific protection of mice against influenza virus infection by local or systemic immunization with bacille Calmette-Gu6rin. J Infect Dis
126: 171, 1977
BOOKS
al: The role of serum haemagglutina-
continued trom page 704
tion-inhibiting antibody in protection against challenge infection with in-
A SYSTEMS APPROACH TO ALCOHOL TREATMENT. Frederick B. Glaser, Stephanie W. Greenberg and Morris Barrett. 303 pp. lIlust. Addiction Research Foundation, Toronto, 1978. $14.95, paperbound. ISBN 0-88868-025-2 TERMINOLOGY OF COMMUNICATION DISORDERS. Speech, Language, Hearing. Lucille Nicolosi, Elizabeth Harryman and Janet Kresheck. 273 pp. IlIust. The Williams & Wilkins Company, Baltimore; Burns & MacEachern Limited. Don Mills, 1978. $17.50, paperbound. ISBN 0-68396500-9 TEXTBOOK OF SPORT FOR THE DISABLED. Ludwig Guttmann. 184 pp. IIlust. Harvey, Miller & Medcalf, Ltd., Oxford, 1976. $16.35. ISBN 0-8560-2055-9 TOCOPHEROL, OXYGEN AND BIOMEMBRANES. Proceedings of the International Symposium on Tocopherol, Oxygen and Biomembranes Held at Lake Yamanaka, Japan, September 2/3, 1977, a Naito Foundation Symposium. Edited by C. de Dave and 0. Hayaishi. 374 pp. lIlust. Elsevier/North-Holland Biomedical Press, Amsterdam, 1978. $46.75. ISBN 0-44480043-3 TRANSPORT IN HIGH RESISTANCE EPITHELIA. Vol. 1, 1977. Thomas W. Ziegler. 176 pp. Eden Press Inc., Montreal, 1977. $18. ISBN 0-88831-012-9 TRAVELERS TO THE TROPICS - GUIDELINES FOR PHYSICIANS. R. Depuis, J. Keystone, J. Losos and others. 36 pp. Illust. International Development Research Centre, Ottawa, 1978. $1.50, paperbound. ISBN 0-88936-166-5 ULTRASONOGRAPHY OF DIGESTIVE DISEASES. Francis S. WeilI. 305 pp. Illust. The C.V. Mosby Company, Saint Louis, 1978. $54. ISBN 0-8016-5374-6
fluenza A2 and B viruses. I Hyg (Camb) 70: 767, 1972 5. STIVER HG, GRAVES P, EICKHOFF TC, et al: Efficacy of "Hong Kong" vac-
cine in preventing "England" variant influenza A in 1972. N Engi I Med
289: 1267, 1973 6. ROBINSON EH, DOWDLE WR: Influenza viruses, in Diagnostic Proce-
dures for Viral and Rickettsial Infections, 4th ed, LENNETrE EH, SCHMIDT NJ (eds), American Public Health Association, New York, 1969, pp
414-33 7. EILBER FR, NIZZE JA, MORTON DL:
Sequential evaluation of general immune competence in cancer patients: correlation with clinical course. Can-
cer 35: 660, 1975 8. HEATH RB, FAIRLEY GH, MALPAS JS:
Production of antibodies against viruses in leukaemia and related diseases. Br I Haematol 10: 365, 1964 9. FEERY BJ, SULLIVAN JR, HURLEY TH, et al: Immunization with influenza vaccine in patients with haematological malignant disease. Med I Aust
1: 292, 1977 10. MEIKLEJOHN G, KEMPE CH, THALMAN WG, et al: Evaluation of monovalent influenza vaccines: observations during influenza A-prime epidemic.
Am I Hyg 55: 12, 1952 11. ORTBALS DW, LIEBHABER H, PRESANT
CA, et al: Influenza immunization of adult patients with malignant diseases. Ann Intern Med 87: 552, 1977 12. LEVIN AG, CUNNINGHAM MP, STEERS
AK, et al: Production of 19S and 7S
738 GMA JOURNAL/OCTOBER 7, 1978/VOL. 119
continued on page 748
Vaccination against influenza has been advocated for certain persons who are at high risk of pneumonic complications of influenza. This group includes the elderly and persons with chronic cardiovascular disease, pulmonary disease, renal disease or diabetes.1 Arguments that influenza vaccine should also be given to cancer patients are based on the facts that undue mortality in this group occurs during influenza epidemics,1'2 and that influenza may cause interruption of cancer therapy for up to several weeks.3 Clearly the titre of serum hemagglutination-inhibiting (HI) antibody correlates with the degree of protection from disease.4'5 Knowledge of the antibody response would therefore be necessary before programs are instituted for administering vaccine to cancer La reponse s6rologique a Ia vaccination avec un vaccin influenza inactive et patients since many of them are rebivalent contenant les antigenes ceiving immunosuppressive drugs, are A/Port Chalmers/I /73 (H3N2) et ill from active disease or may be hyB/Hong Kong/5/72 a et6 mesur6e chez pogammaglobulinemic as a conse44 patients cancereux et chez 27 sujets quence of their disease. Any of these temoins sains. Une augmentation du factors may affect the individual's titre d'anticorps de quatre fois ou plus immune response to vaccination. aprAs Ia vaccination est survenue This study was undertaken to aschez 16 des 44 patients cancereux et sess the serum antibody response to chez 25 des 27 temoins pour l'antigAne A, et chez 14 des 44 patients cancereux influenza A and B vaccine in a group of patients with various malignant et chez 20 des 27 temoins pour l'antig&ne B. Les patients souffrant de diseases in comparison with that in lymphome, qui avalent tendance A healthy vaccinated controls, and to faire de l'hypogamaglobulin6mie, ont determine the relation of the antir6pondu moms bien que les patients body response to chemotherapy, type ayant des tumeurs solides. Chez ces of disease and prognosis.
The serum antibody response to vaccination with bivalent inactivated influenza vaccine containing A/Port Chalmers/I /73 (H3N2) and B/Hong Kong/5/72 antigens was assessed in 44 patIents with cancer and in 27 healthy control subjects. A fourfold or greater increase in antibody titre after vaccination occurred in 16 of the 44 cancer patients and 25 of the 27 controls for the A antigen, and in 14 of the 44 cancer patients and 20 of the 27 controls for the B antigen. Patients with lymphoma, who tended to have hypogammaglobulinemia, responded less well than did patients with solid tumours. Among the latter the failure to show a fourfold or greater increase in antibody titre correlated with a poorer 18-month survival.
derniers l'echec de faire augmenter par quatre fois ou plus le titre d'anticorps 6tait associ6 A une moms bonne survie A 18 mois.
From the departments of medicine and medical microbiology, University of Manitoba, and the sections of infectious diseases and of oncology and hematology, St. Boniface General Hospital, Winnipeg Presented in part at the 17th Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, Oct. 12 to 14, 1977 Reprint requests to: Dr. H. Grant Stiver, Section of infectious diseases, Department of medicine, St. Boniface Hospital, Winnipeg, Man. R2H 2A6
Methods
oral administration of cyclophosphamide, 100 mg/in2, for 14 days starting on day 1. Prevaccination influenza antibody titres were determined on day 1 and the first postvaccination titres 2 to 3 weeks after cyclophosphamide therapy was discontinued (days 28 to 35) and before any further chemotherapy was given. Of the patients 19 had lymphomas, 4 had chronic lymphocytic leukemia, 3 had multiple myeloma, 1 had Waldenstr6m's macroglobulinemia and 1 had polycythemia vera. Of the 19 patients with lymphomas 7 had diffuse well differentiated lymphocytic lymphoma, 6 had nodular poorly differentiated lymphocytic lymphoma, 2 had diffuse poorly differentiated lymphocytic lymphoma, 2 had diffuse histiocytic lymphoma, 1 had diffuse mixed lymphocytic lymphoma, and 1 had nodular sclerosing Hodgkin's disease. Of the 19, 2 had not had chemotherapy for at least 4 weeks at the time of vaccination, 6 were receiving chlorambucil therapy daily and 5 were receiving cyclophosphamide, 400 mg/in2, orally for 5 days. The postvaccination titre was determined more than 2 weeks after the last dose of cyclophosphamide was given. The remaining six patients were receiving 600 mg/in2 of cyclophosphamide and 2 mg of vincristine on days 1 and 8 of a 14-day course of prednisone and procarbazine. The four patients with chronic lymphocytic leukemia were receiving chlorambucil daily at the time of vaccination. The ages of the patients ranged from 32 to 79 years (mean 59 years). Gamma globulin concentrations were noted on the charts of 27 of the patients. In all 44 patients the disease was staged according to standard criteria. The total dose of chemotherapeutic agents and the date of the last dose in relation to that of vaccination were recorded. The second group of vaccinated persons was composed of 27 healthy hospital employees ranging in age from 20 to 49 years (mean 26 years).
Patient population The patient population consisted of two groups. The first was a group of 44 patients with malignant disease being cared for by the section of oncology and hematology, department of medicine, St. Boniface General Hospital, Winnipeg. Of 16 patients who had solid tumours, 13 had metastatic breast carcinoma; all 13 underwent treatment with cyclophosphamide, methotrexate and 5-fluorouracil, which consisted of injections of 5-fluorouracil and methotrexate on days 1 and 8 and CMA JOURNAL/OCTOBER 7, 1978/VOL. 119 733
No member of either group had received influenza vaccine during the previous 2 years. Vaccination procedure In October, November and December 1975 each member of both groups was given a single intramuscular injection of commercially available bivalent aqueous whole-virus influenza vaccine (Fluax, Merck Sharp & Dobme Canada Limited) containing 700 chicken cell agglutinating units of A/Port Chalmers! 1 / 73 (H3N2) and 500 chicken cell agglutinating units of B/Hong Kong! 5/72 antigen. Blood samples for serologic testing were drawn prior to vaccination and again from 2 to 8 weeks afterwards. Measurement of antibody response Samples of serum from patients and controls were paired for simultaneous analysis. By means of the HI test6 with chicken erythrocytes on microtitre plates the samples were tested against the homologous virus strains A/Port Chalmers/ 1 / 73 (H3N2) and B/Hong Kong/5/72, provided by the Laboratory Centre for Disease Control, Ottawa. All serum pairs were inactivated at 560C and treated with receptor-destroying enzyme according to standard procedures.6 Statistical analysis was performed by means of the chi-square test.
in 14 of the 44 cancer patients compared with 20 of the 27 controls (P < 0.001). The geometric mean increase in titre was 2.9 for the cancer patients compared with 8.2 for the controls. Static titres were noted in 24 cancer patients and in 2 controls. The seroconversion rates for patients with different types of malignant disease indicated that the group with lymphomas had a less favourable response than the group with solid tumours to the A/ Port Chalmers antigen. A fourfold or greater increase in antibody titre occurred in only 4 of the 19 patients with lymphomas as opposed to 8 of the 16 patients with solid tumours (P < 0.02). A fourfold increase did not occur in any patient with chronic lymphocytic leukemia, but three of the four patients with malignant monoclonal gammopathies who were receiving chemotherapy did respond.
CONTROL GROUP (n27)
CANCER PATIENTS (n44)
z 0
4
z C., C., 4 I(/)
0 0. w I-
z
Results The numbers of cancer patients and controls who were seronegative (titre of 8 or less) before vaccination were not significantly different (34 of 44 patients and 17 of 27 controls for the A strain, and 39 of 44 and 22 of 27 for the B strain). The serum antibody response to the A/Port Chalmers/i / 73 (H3N2) antigen is illustrated in Fig. 1. A fourfold or greater increase in titre occurred in 16 of the 44 patients with cancer compared with 25 of the 27 controls (P < 0.001). The geometric mean increase in titre was 3.0 for the cancer patients compared with 27.4 for the controls. Static titres were observed in 26 cancer patients but in only 1 control. Similar differences in response to the B/Hong Kong/5/72 antigen were observed (Fig. 2). A fourfold or greater increase in titre occurred
Inexplicably there was no significant difference in response rates to the B antigen between the patients with lymphoma and those with a solid tumour. When survival rates at 18 months after vaccination were analysed there appeared to be some correlation between a fourfold or greater increase in antibody titre and survival, but only in the group with solid tumours. Ten of 12 patients with a fourfold or greater increase in antibody titre in response to either the A or the B antigen were alive at 18 months compared with 3 of 8 patients who did not respond to either antigen. There were no factors other than hypogammaglobulinemia that correlated with failure to respond to vaccination. A low gamma globulin concentration in response to A/Port Chalmers antigen was found in 10 of 18 patients with less than a four-
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8
HI TITRE PREVACCINATION
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HI TITRE PREVACCINATION
FIG. 1-Serum hemagglutination-inhibiting (HI) antibody response to A/Port Chalmers/1/73 (H3N2) antigen. Bottom diagonal line represents no rise in litre, dotted line represents twofold rise, upper line represents fourfold rise. CANCER PATIENTS (n=44)
CONTROL GROUP (n27) S
S
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z C.) C.)
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0 0. w
z 8
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HI TITRE PREVACCINATION
Kong/5/72 antigen. Interpreta-
fold increase in antibody titre, all of whom had lymphoma or chronic lymphocytic leukemia, but in none of 9 patients with a fourfold or greater increase. The mean ages (57.2 and 60.2 years), proportions seronegative before vaccination (81.2% and 75.0%), absolute lymphocyte counts (1.130 and 0.950 x 10'/L) and degrees of fall in the count after chemotherapy, and total cyclophosphamide dose up to the time of vaccination (5150 and 7516 mg) were not significantly different in responders and nonresponders. Although each of the two patients who received remote chemotherapy responded to one antigen, the seven patients with solid tumours who responded to both antigens had received a slightly higher dose of chemotherapeutic agents at the time of vaccination than had the eight patients with such tumours who did not respond to either antigen. Nor was there any difference in seroconversion rates related to whether serum was drawn less than or more than 3 weeks after vaccination. Of the patients with a fourfold or greater increase in antibody titre in response to the A and B antigens 44% and 30% respectively had blood samples drawn less than 3 weeks after vaccination, whereas of those with an increase in titre less than fourfold 30% and 42% respectively had blood samples drawn more than 3 weeks after vaccination. Discussion Several studies in patients with solid neoplasms have shown good correlation between initial cell-mediated immune responsiveness and the subsequent clinical course.. With regard to humoral response, Heath, Fairley and Malpas' demonstrated that the antibody response to Swine, WS, A/England/S 1, A/Singapore! 57 and B/England/59 influenza antigens was poorer than normal in patients with reticuloses, normal in those with acute leukemia, and low in those with multiple myeloma or chronic lymphocytic leukemia. Although local secretory antibodies and other types of humoral antibody such as antineuraminidase and neutralizing antibody, as well as cell-mediated immunity, all play an important role in host defence against influenza, most studies have used serum HI
antibody as an index of the protec- another, where tetanus toxoid was tion afforded by vaccine. Comple- used, it was impaired.'3 In our study ment-fixation antibodies against the the antibody response in patients with nucleoprotein antigen of the influen- solid tumours was impaired in comza virus do not correlate with the parison with that in healthy persons, and within the group with solid tuprotection conferred. The results of our study agree with mours a poor response correlated those of Feery and colleagues,' who with a poorer 18-month survival. found a suboptimal HI antibody re- Lower survival rates in patients with sponse to A/Port Chalmers vaccine solid malignant tumours have been in patients with lymphoma and leuke- found to correlate with poor antibody mia. These authors reported that, response to tetanus toxoid." Other despite a generally retarded response workers have found significantly dein these patients compared with creased rates of antibody response healthy subjects, 83% and 57% of to influenza vaccine in immunosupthe patients achieved satisfactory pressed patients with renal transtitres of antibody to A/Port Chal- plants, but again no correlation with mers and B/Hong Kong vaccine re- the dose of immunosuppressive drugs spectively. However, prevaccination was discovered.'4 Although age may geometric mean titres were already affect the degree of response to in20 or higher in 70% of patients to fluenza vaccine'5 (admittedly our Port Chalmers and in 40% to control group was younger than the B/Hong Kong. In our study, as cancer group) some studies have not shown in Figs. 1 and 2, only 22% been able to correlate diminished reand 11 % of patients had HI titres sponsiveness to tetanus toxoid'2 or equal to or greater than 16 before influenza vaccine'6 with age. vaccination. In the remainder, the The reasons for failure of cancer "seronegative" group, only 21 % and patients to respond to inactivated in36% had probably protective'0 post- fluenza vaccine are unclear. Despite vaccination titres of 16 or greater to the lack of correlation of poor antiA/Port Chalmers and B/Hong Kong body response with dose or type of chemotherapeutic agent, these drugs respectively. In a recent study of the mass vac- probably do play an important role. cination program against swine in- Further studies of the mechanisms fluenza in the United States, an im- of action of vaccine are required, paired antibody response to A/New perhaps with analysis of the function Jersey/ 76 antigen was demonstrated of thymus (T)- and bursa (B)-derived in patients with lymphoreticular and lymphocytes, to help define the host's solid neoplasms." In contrast to our response to these antigens. The relaresults, no difference was found be- tion we found between survival and tween the groups with lymphoreti- a fourfold increase in antibody titre cular and solid tumours in that study in the group with solid tumours sugas to the proportions with a fourfold gests that inability to control tumour increase in antibody titre. A better growth and spread is linked with inseroconversion rate was observed in ability to mount a humoral antibody patients who had pre-existing anti- response, which in turn may be asbody, and when patients received sociated with a defect in the recognivaccine between courses of chemo- tion of antigens by T-lymphocytes. therapy the antibody response was Perhaps a higher degree of immunity not significantly different from that would be conferred by live attenuated of controls. Just as we did, these in- vaccines, but these might cause disvestigators found a significantly de- ease in immunosuppressed hosts. In creased antibody response if vaccine one study a second dose of influenza was given at the time of chemother- vaccine administered 2 weeks after apy but, similarly, no correlation was the first resulted in a fourfold infound between the response and the crease in antibody titre in four of dose of chemotherapeutic drugs or seven patients who had not responded to a single dose.' Adjuvants per se, the absolute lymphocyte count. Additional studies have examined such as bacille Calmette-Gu.rin, the antibody response to other anti- have been shown to heighten protecgens in patients with solid tumours. tion from influenza virus challenge In one of these the antibody response in animals, either by accelerating proto yellow fever vaccine was equal to duction of humoral antibodies or by that in healthy subjects,'2 while in stimulating cell-mediated immunity.'7 CMA JOURNAL/OCTOBER 7, 1978/VOL. 119 735
Nc1.UL (amoxicillin) AMOXIL. (amoxicillin)... A new generation broad-spectrum penicillin. INDICATIONS: Infections due to susceptible strains of the following microorganisms: Gram-negative-H. influenzae, E. coil, R mirabilis and N.gonorrhoeae. Gram-positive-Streptococci, D.pneumoniae and penicillin-sensitive staphylococci. In emergency cases where the causative organism is not yet identified, therapy may be initiated with AMOXIL on the basis of clinical judg ment while awaiting the results of bacteriologic studies. DOSAGE AND ADMINISTRATION: Infections of the ear, nose and throat due to streptococci, pneumococcl, and penicillin-sensitive staphylococci; infections *of the upper respiratory tract due to H. influenzae; in fections of the genitourinary tract due to E. coli, R mirabilis, and S. faecalis; infections of the skin and soft tissues due to streptococci, genicillin-sensitive staphyioc.occi and E. coli: sual Dese: Adults-250 mg every 8 hours. Children-25 mg/kg/day in divided doses every 8 hours. This dosage should not exceed the recommended adult dosage. In severe infections or infections caused by less sensitive organisms: 500 mg every 8 hours for adults, and 50 mg/k9/day in divided doses every 8 hours for children. Infections of the lower respiratory tract due to streptococci, pneumococci, penicillin-sensitive staphylococci and H. influenzae: Usual Dese: Adults-500 mg every 8 hours. Children-50 mg/kg/day in divided doses every 8 hours. This dosage should not exceed the recommended adult dosage. Urethritis due to N. gonorrhoeae: 3 g as a single oral dose. Patients with Qonorrhea, with a suspected lesion of syphilis, should have darkfieid examinations before receiving AMOXIL, and monthly serologic tests for a minimum of four months. For chronic urinary tract infections, frequent bacteriologic and clinical appraisals are necessary. Smaller doses than those recommended above should net be used. Stubborn infections may require several weeks' treatment, sometimes at higher doses than recommended above. Concurrent bacteriolo8 ic sensitivity monitoring is recommended. ontinued clinical and/or bacteriologic follow-up for several months after cessation of therapy may be required. Treatment should continue for 48 to 72 hours beyond the time patient becomes asymptomatic or bacterial eradication is obtained. At least 10 days' treatment is recommended for infections caused by beta-hemolytic streptococci to prevent acute rheumatic fever or glomerulonephritis. CONTRAINDICATION: In patients with a history of allergy to the penicillins or the cephalosporins. PRECAUTIONS: Periodic assessment of renal, hepatic, and hematopoletic function should be made during prolonged AMOXIL therapy. AMOXIL is excreted mostly by the kidney. The dosage administered to patients with renal impairment should be reduced proportionately to the degree of loss of renal function. The possibility of superinfections with mycotic or bacterial organisms should be kept in mind during therapy. If superinfections occur (usually involving Aero bacter, Pseudomonas or Candida), the drug should be discontinued and aproriatetherapy instituted. ADVERSE REACIONS. As with other penicillins, presumably the most common untoward reactions will be related to sensitivity phenomena, similar to those observed with ampicillin. They are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and in those with a history of allergy, asthma, hay fever or urticaria. (See Product Monograph which is available on request).SUPPLI ED: AMOXIL-250 Capsules (250 mg amoxicillin) in bottles of 100 and 500. AMOXIL-500 Capsules (500 mg amoxicillin) in bottles of 100. AMOXIL-125 Suspension(125 mg amoxicillin per 5 ml) in bottles of 75, 100 and 150 ml. AMOXIL-250 Suspension (250 mg amoxicillin per S ml) in bottles of 75, 100 and 150 ml. AMOXIL Pediatric Drops (50 mg amoxicillin per ml) in bottles of 15 ml. AYERST LABORATORIES Division of Ayerst, McKenna & Harrison Limited Montreal, Canada Made In Canada by arrangement with Reg'd BEECHAM INC.
Administration of these agents should be studied in conjunction with influenza vaccination as a possible means of augmenting the humoral antibody response in patients with cancer. We are grateful to James Kennedy for technical assistance and to Janice Coulter for preparation of the manuscript. This work was supported by a grant from the St. Boniface General Hospital Research Foundation.
References 1. EICKHOFF TC, SHERMAN IL, SERFLING
RE: Observations on excess mortality associated with epidemic influenza.
JAMA 176: 776, 1961 2. HouswoRris J, LANGMUIR AD: Excess mortality from epidemic influenza, 1957-1966. Am J Epidemiol 100: 40, 1974 3. FELDMAN 5, WEBSTER RG, SUOG M: Influenza in children and young adults with cancer - 20 cases. Cancer 39: 350, 1977 4. HonsoN D, CURRY RL, BEARE AS, et
antibodies by cancer patients. Clin Exp immunol 7: 839, 1970 13. LYrrON B, HUGHES LE, FULTHORPE AJ: Circulating antibody response in malignant disease. Lancet 1: 69, 1964 14. Snvm. HG, GRAVES P, MEIKLEJOHN G, et al: Impaired serum antibody response to inactivated influenza A and B vaccine in renal transplant recipients. Infect Immun 16: 738, 1977 15. HOWELLS CHL, VESSELINOVA-JENKINS CK, EVANS AD, et al: Influenza vaccination and mortality from bronchopneumonia in the elderly. Lancet 1: 381, 1975 16. FEERY BJ, EVERED MG, MORRISON El: Antibody responses to influenza virus subunit vaccine in the aged. Med J Aust 1: 540, 1976 17. SPENCER JC, GANGULY R, WALDMAN
RH: Nonspecific protection of mice against influenza virus infection by local or systemic immunization with bacille Calmette-Gu6rin. J Infect Dis
126: 171, 1977
BOOKS
al: The role of serum haemagglutina-
continued trom page 704
tion-inhibiting antibody in protection against challenge infection with in-
A SYSTEMS APPROACH TO ALCOHOL TREATMENT. Frederick B. Glaser, Stephanie W. Greenberg and Morris Barrett. 303 pp. lIlust. Addiction Research Foundation, Toronto, 1978. $14.95, paperbound. ISBN 0-88868-025-2 TERMINOLOGY OF COMMUNICATION DISORDERS. Speech, Language, Hearing. Lucille Nicolosi, Elizabeth Harryman and Janet Kresheck. 273 pp. IlIust. The Williams & Wilkins Company, Baltimore; Burns & MacEachern Limited. Don Mills, 1978. $17.50, paperbound. ISBN 0-68396500-9 TEXTBOOK OF SPORT FOR THE DISABLED. Ludwig Guttmann. 184 pp. IIlust. Harvey, Miller & Medcalf, Ltd., Oxford, 1976. $16.35. ISBN 0-8560-2055-9 TOCOPHEROL, OXYGEN AND BIOMEMBRANES. Proceedings of the International Symposium on Tocopherol, Oxygen and Biomembranes Held at Lake Yamanaka, Japan, September 2/3, 1977, a Naito Foundation Symposium. Edited by C. de Dave and 0. Hayaishi. 374 pp. lIlust. Elsevier/North-Holland Biomedical Press, Amsterdam, 1978. $46.75. ISBN 0-44480043-3 TRANSPORT IN HIGH RESISTANCE EPITHELIA. Vol. 1, 1977. Thomas W. Ziegler. 176 pp. Eden Press Inc., Montreal, 1977. $18. ISBN 0-88831-012-9 TRAVELERS TO THE TROPICS - GUIDELINES FOR PHYSICIANS. R. Depuis, J. Keystone, J. Losos and others. 36 pp. Illust. International Development Research Centre, Ottawa, 1978. $1.50, paperbound. ISBN 0-88936-166-5 ULTRASONOGRAPHY OF DIGESTIVE DISEASES. Francis S. WeilI. 305 pp. Illust. The C.V. Mosby Company, Saint Louis, 1978. $54. ISBN 0-8016-5374-6
fluenza A2 and B viruses. I Hyg (Camb) 70: 767, 1972 5. STIVER HG, GRAVES P, EICKHOFF TC, et al: Efficacy of "Hong Kong" vac-
cine in preventing "England" variant influenza A in 1972. N Engi I Med
289: 1267, 1973 6. ROBINSON EH, DOWDLE WR: Influenza viruses, in Diagnostic Proce-
dures for Viral and Rickettsial Infections, 4th ed, LENNETrE EH, SCHMIDT NJ (eds), American Public Health Association, New York, 1969, pp
414-33 7. EILBER FR, NIZZE JA, MORTON DL:
Sequential evaluation of general immune competence in cancer patients: correlation with clinical course. Can-
cer 35: 660, 1975 8. HEATH RB, FAIRLEY GH, MALPAS JS:
Production of antibodies against viruses in leukaemia and related diseases. Br I Haematol 10: 365, 1964 9. FEERY BJ, SULLIVAN JR, HURLEY TH, et al: Immunization with influenza vaccine in patients with haematological malignant disease. Med I Aust
1: 292, 1977 10. MEIKLEJOHN G, KEMPE CH, THALMAN WG, et al: Evaluation of monovalent influenza vaccines: observations during influenza A-prime epidemic.
Am I Hyg 55: 12, 1952 11. ORTBALS DW, LIEBHABER H, PRESANT
CA, et al: Influenza immunization of adult patients with malignant diseases. Ann Intern Med 87: 552, 1977 12. LEVIN AG, CUNNINGHAM MP, STEERS
AK, et al: Production of 19S and 7S
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