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Randomized Trial of Influenza Vaccine With Granulocyte-Macrophage Colony-Stimulating Factor or Placebo in Cancer Patients

From the University of Pittsburgh Cancer Institute, Pittsburgh, PA, and Eastern Virginia Medical School, Norfolk, VA.

Address correspondence to Douglas M. Potter, PhD, University of Pittsburgh Cancer Institute, Biostatistics Facility, Suite 325, Sterling Plaza, 201 N Craig St, Pittsburgh, PA 15213; email: potter{at}upci.pitt.edu; address reprint requests to Ramesh K. Ramanathan, MD, UPMC Cancer Pavillion, 5150 Center Ave, 5th Floor, Pittsburgh, PA 15232; email: ramanathanrk@msx.upmc.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF) would improve response to influenza vaccination in cancer patients.

PATIENTS AND METHODS: In a randomized, patient-blinded, placebo-controlled trial carried out in 1997 to 2000, 133 patients were stratified into five groups of treatment and disease. Single doses of standard split trivalent influenza vaccine and either placebo or 250 µg of GM-CSF were administered at the same time. Hemagglutination inhibition assay titers were measured before and 4 weeks after vaccination.

RESULTS: Standard analyses, which define response as at least a four-fold increase in titers, detect no effect of GM-CSF for any of the three influenza subtypes in the trivalent vaccines (P .12). Analysis that includes the magnitude of the change in titers and combines responses of the subtypes suggests that the placebo group had the greater response (P = .051), thus indicating that GM-CSF does not improve response. Ancillary analyses show that response declines both with increasing age and with higher initial titers. The fraction of patients with at least a four-fold increase in titers was 0.36 (95% confidence interval, 0.29 to 0.42)

CONCLUSION: A single 250-µg dose of GM-CSF administered with the influenza vaccine does not improve response to vaccination. Response in cancer patients is low and declines as age and initial titer increase.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE YEARLY INFLUENZA epidemic is responsible for approximately 20,000 deaths in the United States alone.¹ The Centers for Disease Control and Prevention recommends that individuals at risk for complications of influenza be vaccinated.¹ Although cancer patients are not specifically identified as being at risk, they are frequently older than 50 years and often have suppressed immune systems; for either of these reasons, they would meet the Centers for Disease Control and Prevention definition of increased risk.

Immunosuppression in cancer patients can be caused by the disease itself² or by the transient or persistent effects of therapy. An individual with a suppressed immune system is not only more susceptible to complications of influenza, but also is less responsive to vaccination. Suppressed response to the vaccine has been observed in HIV-infected individuals³ and in cancer patients.⁴ Thus, there is rationale for investigating adjuvants that may enhance response to vaccination in immunosuppressed individuals. One such adjuvant is granulocyte-macrophage colony-stimulating factor (GM-CSF), which stimulates maturation of hematopoietic progenitor cells, induces class II major histocompatibility complex antigen expression on the surface of macrophages, and enhances dendritic cell migration and maturation.⁵ In preclinical studies of interleukin-3 with and without GM-CSF in monkeys, interleukin-3 antibody titers were 8 to 30 times higher in the GM-CSF arm.⁵ However, clinical experience with GM-CSF as an adjuvant has been mixed. Some randomized clinical trials of GM-CSF as an adjuvant to the hepatitis B vaccine have reported substantially increased response to vaccination in the GM-CSF arm,^6-10 whereas others have found no significant effects.^11-13 Preliminary results from a randomized clinical trial using GM-CSF as an adjuvant to the influenza vaccine in elderly people suggested that GM-CSF might improve response.¹⁴ In a randomized trial involving stem-cell transplant patients, some subgroups in the GM-CSF arm had improved response to the influenza vaccine,¹⁵ but there was no overall effect of GM-CSF. The GM-CSF doses in these trials ranged from approximately 20 µg to 300 µg (some trials normalized dose to body-surface area); for our study, we chose a dose of 250 µg administered subcutaneously, which is at the higher end of this range.

Influenza vaccines contain three strains of inactivated whole or split virus (two type A strains and one type B strain).¹⁶ The type A viruses are further classified by variants of the surface proteins hemagglutinin (H) and neuraminidase (N). In recent years, the H1N1 and H3N2 subtypes have been used in the vaccines. During the course of a year, genetic drift creates new virus strains, a few of which dominate each influenza epidemic, and thus, yearly vaccination is required for optimal resistance.¹⁷ The ability to prevent disease is the most direct measure of the efficacy of vaccination; however, in clinical trials, surrogate measures based on antibodies raised against hemagglutinin are often used because the incidence of influenza in unvaccinated subjects is normally low. The concentration of serum antibodies can be measured with the hemagglutination-inhibition (HAI) assay, a dilution assay for which results are expressed as titers. A commonly used surrogate measure of response is the titer ratio; this is defined as t2/t1, where t1 is the initial titer measured before vaccination, and t2 is the final titer measured approximately 4 weeks after vaccination. Titer ratios of 4 or greater are often taken to define response.⁴ An alternative measure of response is the final titer. Final titers of 40 or greater are often considered to be protective^4,18; thus, a subject for whom the initial titer was less than 40 would be considered protected by vaccination if his final titer were 40 or greater.

Because cancer patients are at risk for complications of influenza and respond poorly to vaccination, we sought to determine in a randomized trial whether GM-CSF might improve the response of these patients to the influenza vaccination. A secondary objective was to determine whether the efficacy of the adjuvant was associated with the type or the status of either the cancer or the treatment. In analyzing the trial, we planned to use both the titer ratio and the final titer and to choose statistical approaches matched to the observed characteristics of the data.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Trial Design
The trial was designed to have a 90% power with a level .05 two-sided t test to detect a difference of 10 in mean final HAI titers between the two arms under the assumption that the within-group SD was 20; accrual target was 170 patients. After signing the informed consent form, patients were enrolled onto the trial by the nurse-coordinator and then randomized to receive either the influenza vaccine and recombinant human GM-CSF or the vaccine and placebo. Randomization was implemented by the email randomization service of the University of Pittsburgh Cancer Institute (UPCI) Biostatistics Facility, PA. This automated service is based on software programs that require intervention only to set up the randomization scheme. During the first year of the trial, randomization was unstratified, and the block size was 6; during the second and third years, randomization was stratified according to Table 1 to improve balance within the strata, and a block size of 4 was used. Patients and the laboratory performing the HAI assays were blinded to treatment arm, but the UPCI Biostatistics Facility and nurses responsible for giving the injections were not. The basic analyses were completed in a blinded fashion, but additional checks were carried out after unblinding. We did not assess the success of patient blinding.

Vaccines and Their Administration
The influenza vaccine for the 1997 to 1998 season consisted of the A/Johannesburg/82/96 (H1N1), A/Nanchang/933/95 (H3N2), and B/Harbin/07/94 strains. For the 1998 to 1999 season, it consisted of the A/Beijing/262/95-like (H1N1), A/Sydney/5/97-like (H3N2), and B/Harbin/07/94 strains, and for the 1999 to 2000 season, the A/Beijing/262/95-like (H1N1), A/Sydney/5/97-like (H3N2), and B/Yamanashi/116/98 strains. A 0.5-mL dose of the vaccine, which contained split viruses, was administered intramuscularly in the upper arm of the patient’s choice.

Recombinant human GM-CSF or placebo was administered subcutaneously just before and in the same arm as the influenza vaccine. The dose of GM-CSF was 250 µg in 1 mL of sterile water and was prepared immediately before administration from a powdered formulation. The dose of the placebo was 1 mL of normal saline. Both GM-CSF and placebo were supplied at no cost by Immunex Corporation (Seattle, WA). For patients receiving chemotherapy, it was required that vaccine and adjuvant or placebo be administered at least 1 week before or 1 week after a course of chemotherapy.

Laboratory Investigations
Blood samples for HAI titers were drawn from each patient just before vaccination and 4 weeks (± 3 days) later. Titers were obtained from both samples using the HAI assay performed in the standard manner¹⁹; assays were done at Eastern Virginia Medical School by one of the authors (S.G.). For the 1997 to 1998 influenza season, titers were obtained only for the H1N1 strain, but for the other seasons, they were obtained for all three strains. Initial and final titers for a patient were determined at the same time to minimize assay batch effects. Duplicate assays were performed for each sample using a dilution factor of 2 and starting with a dilution of 1:10 (corresponding to a titer of 10). If the two titers for a patient differed by a factor of 2 or less, the geometric mean of the two was reported. However, if they differed by more than a factor of 2, it was assumed that the assay was invalid, and assays both for the initial and for the final titers were repeated. Titers below the limit of detection were assigned a value of 5.

Measures of Response
We used the titer ratios as the primary measures of response. Some analyses included the magnitude of the titer ratio and/or combined a patient’s responses to the three influenza strains in the vaccine; other analyses defined response as a titer ratio 4. Secondary analyses considered a final titer 40 as protective.

Statistical Procedures
Proportions were compared using Fisher’s exact test or the Mantel-Haenszel test when data were stratified, and the Cochran Q test was used to determine whether an individual’s response was the same for the three influenza strains. We used the Wilcoxon rank sum test to compare the distributions of titer ratios for the two arms; the test was stratified by influenza season, and ranks were computed independently for the three strata. All nonparametric tests were either exact or based on simulations and were performed with StatXact-3 (version 3.1; Cytel Software Corp, Cambridge, MA). For the mean log titer ratios and mean response rates, 95% bias-corrected accelerated (BCa) confidence intervals (CI) were obtained from 10,000 bootstrap samples. Bootstrapping was stratified on influenza season, and the resampling unit was a patient; S-Plus 2000 (MathSoft, Seattle, WA) was used. Generalized estimating equations (GEE) for a binary outcome were used with an unstructured correlation matrix to simultaneously analyze response rates for all influenza subtypes. Proportional odds regression was used to simultaneously analyze all influenza subtypes and include the magnitude of response; the response categories corresponded to the observed values of the titer ratios, which were 2^x/2, where x is an integer. Inference about a variable was based on asymptotic tests of the hypothesis that the regression parameter for the variable was equal to zero; for the proportional odds model, the sandwich estimator was used to account for correlations among responses to the three influenza strains in the vaccine. Stata Release 6 (StataCorp, College Station, TX) was used for these analyses. All statistical tests were two-sided, and P values less than .05 were taken to indicate significant effects. Where results are presented as, for example, 0.33 (0.22 to 0.44), the numbers in parentheses represent the 95% CI.

The rationale for the variety of procedures used to analyze the data was that, although it is important to show results using the simpler conventional approaches, simple approaches seem less well matched to the complexity of the data than the more sophisticated procedures.

	RESULTS

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A total of 133 patients were accrued from October 14, 1997, to November 16, 1999; because accrual was slower than expected, the trial was terminated before the accrual goal was reached. Therapy was well tolerated with only grade 1 erythema or arm soreness. Patient characteristics were as follows: 85 were women, 48 were men, seven were black, 126 were white, median age was 64 years (range, 34 to 87 years), 75 had an ECOG performance status of 0, 54 had an ECOG performance status of 1, and four had an ECOG performance status of 2. Table 1 lists accrual by stratum, year, and arm. Data for 14 patients (seven in each arm) were missing for the following reasons: four patients refused vaccination or refused to have blood samples drawn for titer measurements, five samples froze during shipment, two patients died of progressive cancer, and three samples were not drawn because of an error. If no data were missing, a patient was defined to be assessable. Table 2 shows that the balance of these patients by influenza season and by stratum is excellent. In addition to season and stratum, initial titer and age could also affect response to the vaccination; however, no significant difference between the two arms for either of these variables was observed (P > .6; Wilcoxon rank sum tests).

A measure of response that has been reported by some investigators¹⁴ is the fraction of patients who respond to all three vaccine subtypes. Collapsed over the last two flu seasons, this proportion was 0.14 (95% CI, 0.080 to 0.23). There was no evidence for a treatment effect (P = .15; Fisher’s exact test).

Figure 1 shows the frequencies of titer ratios by influenza subtype and arm collapsed across years and strata. Table 5 lists P values (Wilcoxon rank sum test) for the null hypothesis of no difference between titer ratios for the GM-CSF and placebo arms. For each subtype, the titer ratio for the placebo arm was larger than that for the GM-CSF arm; an indication of this difference are the mean log titer ratios listed in Table 4. Thus, as for the comparison of response rates (Fisher’s exact tests), there is no evidence that GM-CSF improved response; in fact, the evidence suggests the contrary.

View larger version (41K): [in this window] [in a new window]   Fig 1. Frequency of titer ratios by arm and influenza subtype.

A second regression model (proportional odds model) was used to simultaneously analyze titer ratios for the three influenza subtypes in a vaccine. The model is similar to the one described above and contained the same covariates, but it accounts for the magnitude of response. Age (P = 3.2 x 10^-4) and initial titer (P = 1.0 x 10^-9) were both found to be important factors, as above. Responses for strata 1, 3, and 5 also were significantly greater than that for the combination of strata 2 and 4. The P value for the adjuvant effect was .051, with greater response for the placebo arm. (Because titers of 5 correspond to antibody concentrations less than the limit of detection, titer ratios involving a titer of 5 are not interpretable on the ordinal scale used here. If these are eliminated, the P value for the adjuvant effect decreases to .020, and the placebo arm is still favored.)

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In none of the analyses discussed above is there any evidence that GM-CSF improved response to vaccination, and the consistent trend is that the placebo arm had better response. The first analysis presented, although conventional, seems simplistic given the complex nature of the data and thus may be less sensitive than the more sophisticated analyses. The proportional odds analysis may be the most appropriate, despite the facts that more assumptions are required than for the other analyses and that this analysis was neither conventional nor planned. The evidence for this conclusion is that P values for age and initial titer are considerably smaller than for the GEE regression, and only in this model were stratum effects observed to be significant. If the power to detect the effects of these three variables is greater for the proportional odds model, then it is likely that power will also be greater to detect an adjuvant effect. Accepting this conclusion, one would interpret the results of the proportional odds analysis as good evidence that GM-CSF does not increase response to the influenza vaccination in cancer patients.

The conclusion based on analysis with the proportional odds model is stronger than that possible with the first analysis performed with Fisher’s exact test. For the first analysis, the appropriate conclusion is that the null hypothesis that the response rates were the same for the two arms cannot be rejected; however, the CIs for the odds ratios seem to allow substantial adjuvant effects.

Similar analyses based on final titers were also performed; each yielded the conclusion that the null hypothesis could not be rejected. However, we chose to use the titer ratio as the primary measure and to report results for analyses based on it for the following reasons: (1) response, when measured as titer ratio, depends less on initial titer, (2) certain kinds of assay variability are minimized by measuring a change in titers, and (3) use of the final titer as a response measure requires in some analyses that patients with initial titers 40 be excluded and thus results in a loss of 25 patients and creates an imbalance between the arms.

Because the study was not performed in precise accordance with the original design, power calculations based on the actual sample size and analyses are useful. The calculations use the following approximations to the data: titer ratios are distributed exponentially, the within-patient correlation of titer ratios is 0.35 for any pair of influenza subtypes, and the response rate is 0.35 in the placebo arm. Level 0.05 tests with 90% power could detect the following response rates in the GM-CSF arm: 0.68, Fisher’s exact tests for any influenza subtype; 0.60, GEE analysis; 0.61, Wilcoxon tests for any influenza subtype; and 0.56, proportional odds analysis.

In addition to providing information about the efficacy of GM-CSF, some of the analyses discussed above revealed important effects caused by patient variables. In the GEE analysis, we find that for each increase of 10 in initial titer, the odds of response decrease by a factor of 0.66; similarly, for each decade of increase in a patient’s age, the odds of response decrease by a factor of 0.72. For patients of age 35 to 64 years old (the median) the response rate is 0.42 (95% CI, 0.32 to 0.51), whereas for patients of age more than 64 years, it is 0.29 (95% CI, 0.21 to 0.39). Such trends with age and initial titer have been observed previously²⁰ in healthy subjects but have not previously been reported for cancer patients. The overall response rate depended little on the measure of response. This rate was 0.36 (95% CI, 0.29 to 0.42) when response was defined as t2/t1 4, was 0.34 (95% CI, 0.28 to 0.40) when response was defined as t2 40 and t1 less than 40, and was 0.41 (95% CI, 0.35 to 0.47) when response was defined as t2 40 with no restrictions on t1. The last of these numbers may be compared with results for the 1977 to 1978 influenza season.²⁰ For individuals 65 years and older, the response rates ranged from 0.6 to 0.9 for the three different influenza strains. For individuals between the ages of 45 and 64 years, response rates ranged from 0.7 to 0.9. Thus, if the influenza seasons and populations sampled in our trial are comparable to those of²⁰ the 1977 to 1978 season, apart from the disease status of our patients, it seems that the response rate in cancer patients is approximately half that of healthy individuals and that this difference in response rates is not because of age. The lower response rate of cancer patients has been noted before, but previous studies have enrolled no more than approximately half as many cancer patients, and results have been controversial.⁴

Our results are similar to those obtained by Pauksen et al¹⁵ in patients having a stem-cell transplant. There was no significant difference in antibody response to influenza A or B vaccination between 64 patients who received a single dose of GM-CSF and 53 who did not. The fraction of patients in whom antibody titers increased by at least four-fold was similarly low at 0.25 to 0.34.

A generic measure of the immune competence is the absolute lymphocyte count. Pretreatment counts, which were available for 97 patients, ranged from 0.25 to 3.6 x 1,000/mm³ with a median of 1.3 x 1,000/mm³ (one patient with chronic lymphocytic leukemia and a count of 42 x 1,000/mm³ is excluded from this summary). There is evidence from a proportional odds analysis that included terms linear and quadratic in lymphocyte count that response first increased with count and then began to decrease more than 2 x 1,000/mm³ (P < .04 for each term). The increase of response with count seems reasonable, but there is no obvious rationale for the subsequent decrease. However, these analyses were exploratory; hence, the results should be interpreted with caution. Furthermore, a study of lymphocyte subsets, which were not available in this trial, would be of greater use in understanding the immune response to vaccination.²¹

The efficacy of GM-CSF as an adjuvant may depend on the dose and on the timing of administration with respect to vaccination and chemotherapy. In this study, we used a single dose of GM-CSF concurrently with influenza vaccination, and we found that GM-CSF did not increase response to vaccination. Alternative strategies that might improve the immunologic response are multiple doses of GM-CSF before or after influenza vaccination and booster doses²² of influenza vaccination. In addition, new influenza vaccines in development should be evaluated in cancer patients if there is evidence that they have greater efficacy than the standard vaccines. Although our data show that cancer patients have a blunted response to influenza vaccination, a substantial number of patients do derive benefit, and we recommend that all cancer patients receive influenza vaccination annually. However, there is a clear need to evaluate strategies for influenza vaccination in cancer patients.

In summary, there is no evidence from this trial that GM-CSF improves response to influenza vaccination in cancer patients. Analyses that take into account all information about response available from the trial make possible the stronger conclusion that it is unlikely that GM-CSF improves response. Response to influenza vaccine is low in cancer patients and declines as age and initial titer increase.

	ACKNOWLEDGMENTS

 
Supported in part by Immunex Corporation, Seattle, WA, and National Institutes of Health grant no. P30 CA 69855-15 to the University of Pittsburgh Cancer Institute.

We would like to acknowledge the many suggestions made by H. Samuel Wieand.

	NOTES

 
Presented in part at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.

The authors have sole responsibility for trial design, data collection, data analysis, and reporting.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Centers for Disease Control and Prevention: Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (AICP). MMWR Morb Mortal Wkly Rep 49: 1-38, 2000 (No. RR-3)[Medline]

2. Kavanaugh DY, Carbone DP: Immunologic dysfunction in cancer. Hematol Oncol Clin North Am 10: 927-951, 1996[CrossRef][Medline]

3. Kroon FP, van Dissel JT, de Jong JC, et al: Antibody response to influenza, tetanus and pneumococcal vaccines in HIV-seropositive individuals in relation to the number of CD4+ lymphocytes. AIDS 8: 469-476, 1994[Medline]

4. Gross PA, Gould AL, Brown AE: Effect of cancer chemotherapy on the immune response to influenza virus vaccine: Review of published literature. Rev Infect Dis 7: 613-618, 1985[Medline]

5. Jones T, Stern A, Lin R: Potential role of granulocyte-macrophage colony-stimulating factor as vaccine adjuvant. Eur J Clin Microbiol Infect Dis 2: S47-S53, 1994 (suppl 13)

6. Anandh U, Bastani B, Ballal S: Granulocyte-macrophage colony-stimulating factor as an adjuvant to hepatitis B vaccination in maintenance hemodialysis patients. Am J Nephrol 20: 53-56, 2000[CrossRef][Medline]

7. Kapoor D, Aggarwal SR, Singh NP, et al: Granulocyte-macrophage colony-stimulating factor enhances the efficacy of hepatitis B virus vaccine in previously unvaccinated haemodialysis patients. J Viral Hepat 6: 405-409, 1999[CrossRef][Medline]

8. Tarr PE, Lin R, Mueller EA, et al: Evaluation of the tolerability and antibody response after recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and a single dose of hepatitis B vaccine. Vaccine 14: 1199-1204, 1996[CrossRef][Medline]

9. Lakhtakia JR, Jaleel MA, Narayan G, et al: Granulocyte macrophage colony stimulating factor (GM-CSF) induced sero-protection in end stage renal failure patients to hepatitis B in vaccine non-responders. Ren Fail 23: 629-636, 2001[Medline]

10. Sudhagar D, Chandrasekar S, Rao MS, et al: Effect of granulocyte macrophage colony stimulating factor on hepatitis-B vaccination in haemodialysis patients. J Assoc Physicians India 47: 602-604, 1999[Medline]

11. Evans TG, Schiff M, Graves B, et al: The safety and efficacy of GM-CSF as an adjuvant in hepatitis B vaccination of chronic hemodialysis patients who have failed primary vaccination. Clin Nephrol 54: 138-142, 2000[Medline]

12. Hasan MS, Agosti JM, Reynolds KK, et al: Granulocyte-macrophage colony-stimulating factor as an adjuvant for hepatitis B vaccination in healthy adults. J Infect Dis 180: 2023-2026, 1999[CrossRef][Medline]

13. Looney RJ, Hasan MS, Coffin D, et al: Hepatitis B immunization of healthy elderly adults: Relationship between naïve CD4+ T cells and primary immune response and evaluation of GM-CSF as an adjuvant. J Clin Immunol 21: 30-36, 2001[CrossRef][Medline]

14. Taglietti M, Rouzier-Panis R, Aymard M, et al: A double-blind placebo-controlled study to assess the immune response to flu vaccine following a single dose of rhGM-CSF in elderly people. Abstracts of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, FL, October 4-7, 1994, p 266

15. Pauksen K, Linde A, Hammarstrom V, et al: Granulocyte-macrophage colony-stimulating factor as immunomodulating factor together with influenza vaccination in stem cell transplant patients. Clin Infect Dis 30: 342-348, 2000[Medline]

16. Wood AJJ: Prevention and treatment of influenza. N Engl J Med 24: 1778-1787, 2000

17. Stamboulian D, Bonvehi PE, Nacinovich FM, et al: Influenza. Infect Dis Clin North Am 14: 141-166, 2000[CrossRef][Medline]

18. Hermogenes AW, Gross PA: Influenza virus vaccine: A need for emphasis. Semin Respir Infect 7: 54-60, 1992[Medline]

19. The hemagglutination inhibition test for influenza viruses (pamphlet). Atlanta GA, US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, December 1975 (revised May 1981)

20. La Montagne JR, Noble GR, Quinnan GV, et al: Summary of clinical trials of inactivated influenza vaccine: 1978. Rev Infect Dis 5: 723-736, 1983[Medline]

21. Green TF, Jaffee EM: Cancer vaccines. J Clin Oncol 17: 1047-1060, 1999[Abstract/Free Full Text]

22. Lo W, Whimbey E, Elting L, et al: Antibody response to a two-dose influenza regimen in adult lymphoma patients on chemotherapy. Eur J Clin Microbiol Infect Dis 10: 778-782, 1993

Submitted February 11, 2002; accepted July 15, 2002.

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