THE JOUR;\fAL OF INFECTIOUS DISEASE. VOL. 136, SUPPLEMENT • DECB1BER 1977
© 1977 by the University of Chicago. All rights reserved.
Swine Influenza Virus Vaccination in Patients with Multiple Sclerosis From the Multiple Sclerosis Research Clinic, Department of Neurology, Reed Neurological Research Center, UCLA Center for the Health Sciences, Los Angeles, California; the Infectious Disease Branch, National Institute of Neurological and Communicative Diseases and Stroke, National Institutes of Health, Bethesda, Maryland; and the Respiratory Virology Branch, Center for Disease Control, Atlanta, Georgia
Lawrence W. Myers, George W. Ellison, Morris Lucia, Steven N ovom, Marie Holevoet, David Madden, John Sever, and Gary R. Noble
Multi ple sclerosis (MS), a chronic degenerative disease of the central nervous system (CNS) of unknown etiology, is characterized pathologically by multiple patchy areas of demyelination and sclerosis throughout the white matter of the CNS [1]. It is characterized clinically by relapses and remissions, although not invariably [2]. A relapse may be defined as a worsening of symptoms and signs lasting for more than 24 hr and not attributable to fever or other intercurrent diseases [2]. A relapse generally implies a new area of demyelination in the CNS, although
This work was funded by contract no. NOI AI-62515 from the National Institute of Allergy and Infectious Diseases and the National Institute of Neurological and Communicative Diseases and Stroke, National Institutes of Health. The technical assistance of Harrie Ann Sutton and Leola Murray and the secretarial assistance of Janice Grace and Patricia Jeffryes are acknowledged. Please address requests for reprints to Dr. Lawrence W. Myers, Department of Neurology, Reed Neurological Research Center, UCLA Center for the Health Sciences, Los Angeles, California 90024.
5546
there are those who argue that symptoms and signs may occur without demyelination [3]. It is generally accepted that various stresses such as fatigue, trauma, emotional stress, infection, and immunization may act as precipitating factors that induce the first or subsequent "attacks" (relapses and/or exacerbations) of MS [4]. Because of isolated reports of patients with MS who experience their first or subsequent attack after immunization with various vaccines [5-7], many physicians advise their patients with MS not to be immunized. However, this recommendation has not been based upon any carefully controlled study, and in view of the rarity of neurological sequelae following immunization, these reported attacks may have occurred coincidentally with the immunizations. There have been three uncontrolled studies of influenza virus vaccination in patients with MS, which suggest that immunization does not precipitate attacks of MS. Sibley and Foley [8] performed a study in which 24 patients with MS were vaccinated against four strains of influenza virus. Most patients re-
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 31, 2015
A double-blind, placebo-controlled study was conducted to evaluate the safety and efficacy of inactivated influenza virus vaccines in patients with multiple sclerosis. The vaccine used contained 200 chick cell-agglutinating (CCA) units of influenza A/New Jersey/76 and 200 CCA units of influenza A/Victoria/75 whole viruses (Merrell-National Laboratories, Cincinnati, Ohio). The frequency of clinical relapses of multiple sclerosis was the same in the vaccine-treated (four of 33 patients) and placebo-treated (four of 33) groups. An untreated control group had a slightly higher rate of relapses (four of 22). Toxic reactions to the vaccine were not a significant problem. The efficacy of the vaccination as measured by titers of hemagglutination-inhibiting antibody was comparable to that reported for the general population. However, patients with preexisting antibody were less responsive to the vaccine than normal controls studied previously. The patients who did not respond to the vaccine tended to be older and more disabled. There were no changes in titers of antibody to rubeola or rubella virus after vaccination or in relation to change in clinical course. It is concluded that the vaccine is safe and effective in patients with multiple sclerosis.
5547
Vaccination of Multiple Sclerosis Patients
ceived two doses at two-week intervals. The vaccination appeared to be efficacious as judged by the rise in titers of antibody, although the actual percentage of seroconversions was not reported. Two patients had a temporary worsening of their neurological symptoms in relation to a febrile reaction to the vaccination. One patient developed a new attack of retrobulbar neuritis --24 hr after vaccination. That patient had had frequent attacks in the preceeding three years, and the authors felt that a single relapse following influenza vaccination was probably fortuitous Davis et al. [9] administered a bivalent influenza virus vaccine to 23 patients with MS. Eleven of these patients had been treated with immunosuppressive drugs for a minimum of 11 months prior to vaccination. The other 12 patients had been placebo-treated controls. Of the 23 patients 22 received two doses of vaccine at onemonth intervals. There was a relatively poor response to the vaccine, with only six of 11 patients in the immunosuppressive drug-treated group and seven of 12 in the placebo-treated group developing a fourfold or greater rise in titer of antibody in serum one month after the second immunization. No adverse effects from these vaccinations were reported [9] (D. K. Ziegler, personal communication). In a retrospective analysis Sibley er al. [10] studied 93 patients who had received a total of 209 doses of influenza virus vaccine between 1962 and 1975. Only one patient developed evidence of a new lesion within a month after vaccination. The rate of relapse was less than that which would have been expected in the natural course of the disease. Most patients tolerated vaccination well, and the frequency of toxic (7% of the patients) and allergic (0.5%) reactions was similar to that reported for the general population. The investigators pointed out that influenza is often a very debilitating experience for the MS patient, and they concluded that influenza constitutes a greater threat than that of mild reactions to vaccination. Because of the potential threat of a serious epidemic of influenza due to swine influenza virus, a national campaign to immunize most of the adult population of the United States against that virus was launched in the spring of 1976.
Materials and Methods
Selection ot subjects. Volunteers for this study were solicited from patients with MS who attended the MUltiple Sclerosis Research Clinic of the Reed Neurological Research Center (UCLA Center for the Health Sciences. Los Angeles, Cali£.) or the Multiple Sclerosis Clinic of the Harbor General Hospital (Los Angeles), or who were private patients of a neurologist on the staff of the UCLA Center for the Health Sciences. Patients with a history of an allergic reaction to eggs or to influenza virus vaccines were excluded from the study to avoid the increased risk of another allergic reaction. Patients who were younger than 24 years of age or who were receiving corticosteroids or other immunomodulating drugs were also excluded because the antibody responses in these individuals might have been poor. Informed consent was obtained from each participant. The study was conducted in two parts. The first part was a pilot study in which 10 patients received vaccine and 10 patients received placebo. The second part included 23 patients who received vaccine, 23 patients who received placebo, and 22 patients who did not receive any injection (untreated controls). Assignment to subgroups. Subjects were assigned to the vaccine treatment group or placebo treatment group by a restrictive randomization technique: i.e., on the day of injection the neurologist examining the patient assigned the patient to an active group if (1) the patient had had a relapse within the preceeding three months or (2) the patient had been getting progressively worse within the preceeding six months; otherwise, the patient was assigned to an inactive group. Patients within each of these two subgroups, namely, (1) clinically active and (2) clinically inactive, were then randomly assigned to receive an injection of one of the two
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 31, 2015
[8].
Since there was a possibility that mass immunization of MS patients might precipitate a rash of relapses, this campaign evoked great concern among neurologists caring for patients with MS. Therefore, it was decided that a carefully controlled, double-blind study was needed to evaluate the safety and efficacy of the swine influenza virus vaccine in patients with MS.
8548
rection of one of us (G.N.). Sera obtained for determination of titers of antibody to rubeola and rubella viruses were shipped in a similar manner to the neurovirology laboratory of the National Institute of Neurological and Communicative Disorders and Stroke (National Institutes of Health, Bethesda, Md.) where assays of HAl antibody were performed under the direction of one of us (D.M.). All sera were coded and tested blindly. Sera obtained before, three weeks after, and three months after treatment were tested on the same day with the same set of reagents to reduce technical variability. Systemic reaction score (SRS). The SRS was calculated by methods described previously [12]. Subjective symptoms were assigned a weighted score (no reaction 0, mild 1+, moderate 2+, and severe = 3+). The sum of these scores within each group was divided by the number of participants in the group to derive the SRS for that group.
=
=
=
Table 1. Characteristics of patients with multiple sclerosis according to treatment group. Characteristic Age (years) Mean Range Sex * Female Male Age (years) at onset of disease Mean Range Duration of disease (years) Mean Range Type of course * Relapsing Relapsing-progressive Progressive Phase of disease * Stationary Remission Progression Degree of disability'[ Mean Range
Influenza vaccine
Placebo Untreated
43 26-64
43 25-64
44 22-61
25 (76) 8 (24)
19 (58) 14 (42)
14 (64) 8 (36)
25 10-42
30 13-46
32 18-52
17 1-41
13 1-35
12 1-31
18(55) 11 (33) 4 (12)
20 (61) 11 (33) 2 (6)
12 (55) 8 (36) 2 (9)
26 (78) 3 (9) 4 (12)
26 (79) 1 (3) 6 (18)
16 (73) 1 (5) 5 (22)
4.1 1.0-9.0
4.4 1.0-8.0
5.3 1.0-9.0
*Data are numbers of subjects. Numbers in parentheses represent percentage of total. tSee [11] for derivation of score.
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 31, 2015
possible vaccines (virus or placebo). The randomization schedule was provided by the Bureau of Biologics (Food and Drug Administration, Bethesda, Md.). The patients, the nurse administering the vaccine, and the neurologists evaluating the patients did not know which vaccine was administered. The code was kept by one of us (D. M.) who was not in contact with the patients or involved in evaluation of the patients. Injection procedure. On the day of injection, no patient was febrile or had symptoms or signs of infection. A neurological evaluation was performed by a neurologist (L.M., G.E., M.L., or S.N.), and the patient was classified according to the course and phase of disease and was assigned a functional systems and disability status score (DSS) [l l]. A sample of venous blood was collected, and serum was stored at -20 C for subsequent antibody studies. A 0.5-ml injection of coded vaccine or placebo was then administered into the deltoid muscle. The vaccine contained 200 chick cell-agglutinating (CCA) units of whole, killed A/New Jersey (NJ)/76 influenza virus and 200 CCA units of whole, killed A/Victoria/75 influenza virus in a diluent of phosphate-buffered saline with thiomerosal as preservative (Merrell-National Laboratories, Cincinnati, Ohio). The placebo consisted of diluent without virus. The vials were coded and labeled by personnel at the Bureau of Biologics. Each patient was observed for 15 min for any immediate adverse effect and then released. That evening the patient recorded his/her oral temperature. The patients were directed to take aspirin or acetaminophen for fever or malaise. Each patient returned to the clinic the next day, and the oral temperature was again measured. Local and systemic symptoms and signs were recorded, and the patient was advised to report any further adverse reactions by telephone. Each patient was reevaluated by the neurologist, and a sample of blood was drawn for determination of antibody titers three weeks after. and three months after injection. Determination of titers of serum antibody. Sera obtained for determination of titers of antibody to A/NJ /76 and A/Victoria/75 viruses were shipped in dry ice to the Center for Disease Control (Atlanta, Ga.) where assays of HAl antibody were performed under the di-
Myers et al.
Vaccination of Multiple Sclerosis Patients
5549
Results
Table 2.
Frequency and severity of local and systemic reactions in patients given placebo or influenza vaccine. No. of vaccine-treated patients with indicated score
No. of placebo-treated patients with indicated score Reaction Symptom Local pain, burning Malaise, myalagia, weakness Headache Nausea, vomiting Sign Fever Redness Induration Tenderness
0
1+
2+
3+
0
1+
2+
3+
28 29 30 29
3 3 1 3
2 1 0 1
0 0 2 0
28 23 26 29
3 6 5 3
2 3 0 1
0 1 2 0
33 33 33 32
0 0 0 0
0 0 0 1
0 0 0 0
33 31 32 29
0 1 1 2
0 1 0 2
0 0 0 0
NOTE. The vaccine contained 200 chick cell-agglutinating (CCA) units of whole, killed influenza A/New Jersey/76 virus and 200 CCA units of whole, killed influenza A/Victoria/75 virus (Merrell-National Laboratories, Cincinnati, Ohio). The following weighted scores were used to indicate severity of the reaction: 0 = no reaction; 1+ = mild; 2+ = moderate; and 3+ = severe. The systemic reaction score, which was 0.5 for the placebo-treated patients and 0.9 for the vaccine-treated patients, was derived by assigning a weighted score to the subjective symptoms, adding up the scores within each group, and dividing this sum by the number of participants in the group.
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 31, 2015
Pilot study. Analysis of the data, obtained three weeks after treatment, from the pilot study in which 10 patients had received vaccine and 10 patients had received placebo revealed that local and systemic reactions to the vaccine were all mild (SRS = 0.5) and were comparable to those recorded in the placebo-treated group (SRS = 0.5). A mild relapse (facial weakness) had occurred in a vaccine-treated patient, whereas one moderate relapse (leg weakness and unsteady gait) and one severe relapse (quadriparesis) had developed in placebo-treated patients. We decided to proceed with part two of the study and to include an untreated control group of pc. .ients in the neurological studies. The charactcristics of the patients in the three subgroups (vaccine-treated, placebo-treated, and untreated) were generally comparable (table 1). There were more females in the vaccine-treated group than in the placebo-treated group. Local and systemic reactions. The frequency and severity of local and systemic reactions in the placebo- and vaccine-treated groups are summarized in table 2. The majority of patients denied any adverse effect from the vaccine, and the reactions reported were generally mild, transient, and inconsequential. Eight (25%) of the patients receiving placebo and 17 (52%) of the
patients receIVIng vaccine reported some type of symptom. Although some patients felt feverish, no temperature of >38 C was recorded. The vaccine-treated group had a SRS of 0.9, and the placebo-treated group had a SRS of 0.5. No local or systemic reaction required treatment beyond aspirin or acetaminophen. One patient who received the vaccine developed a mild, immediate hypersensitivity reaction that was manifested by local pain and a local area of erythema (1 em) within minutes of receiving the vaccine. The reaction subsided within hours. No systemic allergic reactions occurred. One patient experienced a temporary exacerbation (lasting for
© 1977 by the University of Chicago. All rights reserved.
Swine Influenza Virus Vaccination in Patients with Multiple Sclerosis From the Multiple Sclerosis Research Clinic, Department of Neurology, Reed Neurological Research Center, UCLA Center for the Health Sciences, Los Angeles, California; the Infectious Disease Branch, National Institute of Neurological and Communicative Diseases and Stroke, National Institutes of Health, Bethesda, Maryland; and the Respiratory Virology Branch, Center for Disease Control, Atlanta, Georgia
Lawrence W. Myers, George W. Ellison, Morris Lucia, Steven N ovom, Marie Holevoet, David Madden, John Sever, and Gary R. Noble
Multi ple sclerosis (MS), a chronic degenerative disease of the central nervous system (CNS) of unknown etiology, is characterized pathologically by multiple patchy areas of demyelination and sclerosis throughout the white matter of the CNS [1]. It is characterized clinically by relapses and remissions, although not invariably [2]. A relapse may be defined as a worsening of symptoms and signs lasting for more than 24 hr and not attributable to fever or other intercurrent diseases [2]. A relapse generally implies a new area of demyelination in the CNS, although
This work was funded by contract no. NOI AI-62515 from the National Institute of Allergy and Infectious Diseases and the National Institute of Neurological and Communicative Diseases and Stroke, National Institutes of Health. The technical assistance of Harrie Ann Sutton and Leola Murray and the secretarial assistance of Janice Grace and Patricia Jeffryes are acknowledged. Please address requests for reprints to Dr. Lawrence W. Myers, Department of Neurology, Reed Neurological Research Center, UCLA Center for the Health Sciences, Los Angeles, California 90024.
5546
there are those who argue that symptoms and signs may occur without demyelination [3]. It is generally accepted that various stresses such as fatigue, trauma, emotional stress, infection, and immunization may act as precipitating factors that induce the first or subsequent "attacks" (relapses and/or exacerbations) of MS [4]. Because of isolated reports of patients with MS who experience their first or subsequent attack after immunization with various vaccines [5-7], many physicians advise their patients with MS not to be immunized. However, this recommendation has not been based upon any carefully controlled study, and in view of the rarity of neurological sequelae following immunization, these reported attacks may have occurred coincidentally with the immunizations. There have been three uncontrolled studies of influenza virus vaccination in patients with MS, which suggest that immunization does not precipitate attacks of MS. Sibley and Foley [8] performed a study in which 24 patients with MS were vaccinated against four strains of influenza virus. Most patients re-
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 31, 2015
A double-blind, placebo-controlled study was conducted to evaluate the safety and efficacy of inactivated influenza virus vaccines in patients with multiple sclerosis. The vaccine used contained 200 chick cell-agglutinating (CCA) units of influenza A/New Jersey/76 and 200 CCA units of influenza A/Victoria/75 whole viruses (Merrell-National Laboratories, Cincinnati, Ohio). The frequency of clinical relapses of multiple sclerosis was the same in the vaccine-treated (four of 33 patients) and placebo-treated (four of 33) groups. An untreated control group had a slightly higher rate of relapses (four of 22). Toxic reactions to the vaccine were not a significant problem. The efficacy of the vaccination as measured by titers of hemagglutination-inhibiting antibody was comparable to that reported for the general population. However, patients with preexisting antibody were less responsive to the vaccine than normal controls studied previously. The patients who did not respond to the vaccine tended to be older and more disabled. There were no changes in titers of antibody to rubeola or rubella virus after vaccination or in relation to change in clinical course. It is concluded that the vaccine is safe and effective in patients with multiple sclerosis.
5547
Vaccination of Multiple Sclerosis Patients
ceived two doses at two-week intervals. The vaccination appeared to be efficacious as judged by the rise in titers of antibody, although the actual percentage of seroconversions was not reported. Two patients had a temporary worsening of their neurological symptoms in relation to a febrile reaction to the vaccination. One patient developed a new attack of retrobulbar neuritis --24 hr after vaccination. That patient had had frequent attacks in the preceeding three years, and the authors felt that a single relapse following influenza vaccination was probably fortuitous Davis et al. [9] administered a bivalent influenza virus vaccine to 23 patients with MS. Eleven of these patients had been treated with immunosuppressive drugs for a minimum of 11 months prior to vaccination. The other 12 patients had been placebo-treated controls. Of the 23 patients 22 received two doses of vaccine at onemonth intervals. There was a relatively poor response to the vaccine, with only six of 11 patients in the immunosuppressive drug-treated group and seven of 12 in the placebo-treated group developing a fourfold or greater rise in titer of antibody in serum one month after the second immunization. No adverse effects from these vaccinations were reported [9] (D. K. Ziegler, personal communication). In a retrospective analysis Sibley er al. [10] studied 93 patients who had received a total of 209 doses of influenza virus vaccine between 1962 and 1975. Only one patient developed evidence of a new lesion within a month after vaccination. The rate of relapse was less than that which would have been expected in the natural course of the disease. Most patients tolerated vaccination well, and the frequency of toxic (7% of the patients) and allergic (0.5%) reactions was similar to that reported for the general population. The investigators pointed out that influenza is often a very debilitating experience for the MS patient, and they concluded that influenza constitutes a greater threat than that of mild reactions to vaccination. Because of the potential threat of a serious epidemic of influenza due to swine influenza virus, a national campaign to immunize most of the adult population of the United States against that virus was launched in the spring of 1976.
Materials and Methods
Selection ot subjects. Volunteers for this study were solicited from patients with MS who attended the MUltiple Sclerosis Research Clinic of the Reed Neurological Research Center (UCLA Center for the Health Sciences. Los Angeles, Cali£.) or the Multiple Sclerosis Clinic of the Harbor General Hospital (Los Angeles), or who were private patients of a neurologist on the staff of the UCLA Center for the Health Sciences. Patients with a history of an allergic reaction to eggs or to influenza virus vaccines were excluded from the study to avoid the increased risk of another allergic reaction. Patients who were younger than 24 years of age or who were receiving corticosteroids or other immunomodulating drugs were also excluded because the antibody responses in these individuals might have been poor. Informed consent was obtained from each participant. The study was conducted in two parts. The first part was a pilot study in which 10 patients received vaccine and 10 patients received placebo. The second part included 23 patients who received vaccine, 23 patients who received placebo, and 22 patients who did not receive any injection (untreated controls). Assignment to subgroups. Subjects were assigned to the vaccine treatment group or placebo treatment group by a restrictive randomization technique: i.e., on the day of injection the neurologist examining the patient assigned the patient to an active group if (1) the patient had had a relapse within the preceeding three months or (2) the patient had been getting progressively worse within the preceeding six months; otherwise, the patient was assigned to an inactive group. Patients within each of these two subgroups, namely, (1) clinically active and (2) clinically inactive, were then randomly assigned to receive an injection of one of the two
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 31, 2015
[8].
Since there was a possibility that mass immunization of MS patients might precipitate a rash of relapses, this campaign evoked great concern among neurologists caring for patients with MS. Therefore, it was decided that a carefully controlled, double-blind study was needed to evaluate the safety and efficacy of the swine influenza virus vaccine in patients with MS.
8548
rection of one of us (G.N.). Sera obtained for determination of titers of antibody to rubeola and rubella viruses were shipped in a similar manner to the neurovirology laboratory of the National Institute of Neurological and Communicative Disorders and Stroke (National Institutes of Health, Bethesda, Md.) where assays of HAl antibody were performed under the direction of one of us (D.M.). All sera were coded and tested blindly. Sera obtained before, three weeks after, and three months after treatment were tested on the same day with the same set of reagents to reduce technical variability. Systemic reaction score (SRS). The SRS was calculated by methods described previously [12]. Subjective symptoms were assigned a weighted score (no reaction 0, mild 1+, moderate 2+, and severe = 3+). The sum of these scores within each group was divided by the number of participants in the group to derive the SRS for that group.
=
=
=
Table 1. Characteristics of patients with multiple sclerosis according to treatment group. Characteristic Age (years) Mean Range Sex * Female Male Age (years) at onset of disease Mean Range Duration of disease (years) Mean Range Type of course * Relapsing Relapsing-progressive Progressive Phase of disease * Stationary Remission Progression Degree of disability'[ Mean Range
Influenza vaccine
Placebo Untreated
43 26-64
43 25-64
44 22-61
25 (76) 8 (24)
19 (58) 14 (42)
14 (64) 8 (36)
25 10-42
30 13-46
32 18-52
17 1-41
13 1-35
12 1-31
18(55) 11 (33) 4 (12)
20 (61) 11 (33) 2 (6)
12 (55) 8 (36) 2 (9)
26 (78) 3 (9) 4 (12)
26 (79) 1 (3) 6 (18)
16 (73) 1 (5) 5 (22)
4.1 1.0-9.0
4.4 1.0-8.0
5.3 1.0-9.0
*Data are numbers of subjects. Numbers in parentheses represent percentage of total. tSee [11] for derivation of score.
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 31, 2015
possible vaccines (virus or placebo). The randomization schedule was provided by the Bureau of Biologics (Food and Drug Administration, Bethesda, Md.). The patients, the nurse administering the vaccine, and the neurologists evaluating the patients did not know which vaccine was administered. The code was kept by one of us (D. M.) who was not in contact with the patients or involved in evaluation of the patients. Injection procedure. On the day of injection, no patient was febrile or had symptoms or signs of infection. A neurological evaluation was performed by a neurologist (L.M., G.E., M.L., or S.N.), and the patient was classified according to the course and phase of disease and was assigned a functional systems and disability status score (DSS) [l l]. A sample of venous blood was collected, and serum was stored at -20 C for subsequent antibody studies. A 0.5-ml injection of coded vaccine or placebo was then administered into the deltoid muscle. The vaccine contained 200 chick cell-agglutinating (CCA) units of whole, killed A/New Jersey (NJ)/76 influenza virus and 200 CCA units of whole, killed A/Victoria/75 influenza virus in a diluent of phosphate-buffered saline with thiomerosal as preservative (Merrell-National Laboratories, Cincinnati, Ohio). The placebo consisted of diluent without virus. The vials were coded and labeled by personnel at the Bureau of Biologics. Each patient was observed for 15 min for any immediate adverse effect and then released. That evening the patient recorded his/her oral temperature. The patients were directed to take aspirin or acetaminophen for fever or malaise. Each patient returned to the clinic the next day, and the oral temperature was again measured. Local and systemic symptoms and signs were recorded, and the patient was advised to report any further adverse reactions by telephone. Each patient was reevaluated by the neurologist, and a sample of blood was drawn for determination of antibody titers three weeks after. and three months after injection. Determination of titers of serum antibody. Sera obtained for determination of titers of antibody to A/NJ /76 and A/Victoria/75 viruses were shipped in dry ice to the Center for Disease Control (Atlanta, Ga.) where assays of HAl antibody were performed under the di-
Myers et al.
Vaccination of Multiple Sclerosis Patients
5549
Results
Table 2.
Frequency and severity of local and systemic reactions in patients given placebo or influenza vaccine. No. of vaccine-treated patients with indicated score
No. of placebo-treated patients with indicated score Reaction Symptom Local pain, burning Malaise, myalagia, weakness Headache Nausea, vomiting Sign Fever Redness Induration Tenderness
0
1+
2+
3+
0
1+
2+
3+
28 29 30 29
3 3 1 3
2 1 0 1
0 0 2 0
28 23 26 29
3 6 5 3
2 3 0 1
0 1 2 0
33 33 33 32
0 0 0 0
0 0 0 1
0 0 0 0
33 31 32 29
0 1 1 2
0 1 0 2
0 0 0 0
NOTE. The vaccine contained 200 chick cell-agglutinating (CCA) units of whole, killed influenza A/New Jersey/76 virus and 200 CCA units of whole, killed influenza A/Victoria/75 virus (Merrell-National Laboratories, Cincinnati, Ohio). The following weighted scores were used to indicate severity of the reaction: 0 = no reaction; 1+ = mild; 2+ = moderate; and 3+ = severe. The systemic reaction score, which was 0.5 for the placebo-treated patients and 0.9 for the vaccine-treated patients, was derived by assigning a weighted score to the subjective symptoms, adding up the scores within each group, and dividing this sum by the number of participants in the group.
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on August 31, 2015
Pilot study. Analysis of the data, obtained three weeks after treatment, from the pilot study in which 10 patients had received vaccine and 10 patients had received placebo revealed that local and systemic reactions to the vaccine were all mild (SRS = 0.5) and were comparable to those recorded in the placebo-treated group (SRS = 0.5). A mild relapse (facial weakness) had occurred in a vaccine-treated patient, whereas one moderate relapse (leg weakness and unsteady gait) and one severe relapse (quadriparesis) had developed in placebo-treated patients. We decided to proceed with part two of the study and to include an untreated control group of pc. .ients in the neurological studies. The charactcristics of the patients in the three subgroups (vaccine-treated, placebo-treated, and untreated) were generally comparable (table 1). There were more females in the vaccine-treated group than in the placebo-treated group. Local and systemic reactions. The frequency and severity of local and systemic reactions in the placebo- and vaccine-treated groups are summarized in table 2. The majority of patients denied any adverse effect from the vaccine, and the reactions reported were generally mild, transient, and inconsequential. Eight (25%) of the patients receiving placebo and 17 (52%) of the
patients receIVIng vaccine reported some type of symptom. Although some patients felt feverish, no temperature of >38 C was recorded. The vaccine-treated group had a SRS of 0.9, and the placebo-treated group had a SRS of 0.5. No local or systemic reaction required treatment beyond aspirin or acetaminophen. One patient who received the vaccine developed a mild, immediate hypersensitivity reaction that was manifested by local pain and a local area of erythema (1 em) within minutes of receiving the vaccine. The reaction subsided within hours. No systemic allergic reactions occurred. One patient experienced a temporary exacerbation (lasting for
