THE JOURNAL OF INFECTIOUS DISEASES • VOL. 133, NO.6· © 1976 by the University of Chicago. All rights reserved.
JUNE 1976
From the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the Center for Disease Control, and the Bureau of Biologics of the Food and Drug Administration A Status Report on National Immunization against Influenza It is important that the medical profession know and understand the course of events related to national immunization against influenza since such events will certainly recur whenever the nation is threatened with pandemic influenza. Memory is short, and it is worth saying that this is the third, not the first, national program to immunize the public or at least a large segment of it against the threat of a pandemic. Lessons gleaned from the inadequacies of the earlier efforts were influential in the current decisions. Basis for Decision
In 1957, when the Asian (H2N2) influenza virus emerged in the Far East, it was recognized as a double antigenic shift (from HINl). The U.S. Public Health Service in cooperation with State and Territorial Health Officers and the pharmaceutical industry initiated a program to immunize the public with a monovalent vaccine. Again in 1968, when the Hong Kong A Strain (H3N2) emerged, a similar decision was made. In both events, vaccine distribution and administration was left to the private sector with the federal government only making recommendations to industry, health officials, and the public. Both efforts must be regarded as failures insofar as the public at large is concerned. In 1957, vaccine production began in June; by mid-November 48.8 million doses of vaccine had been distributed [1]. Unfortunately, the highly visible impact of the epidemic as represented by school closings, industrial absenteeism, and a shortage of hospital beds occurred between September and early November, and demands for the vaccine
Please address requests for reprints to Dr. John R. Seal, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20014.
715
Downloaded from http://jid.oxfordjournals.org/ at Sheffield University on September 7, 2015
ended shortly afterward. Yet more than a third of the estimated 60,000 deaths attributed to that pandemic in the United States occurred between January and March 1958. Another 20,000 deaths occurred in 1960; this number might have been reduced had the still susceptible population been immunologically introduced to the virus by a killed vaccine instead of a live wild virus [2]. The experience of 1968-1969, was similar although less dramatic (30,000 deaths vs. 60,000 in 1957-1958), but an estimated 51 million Americans were ill, the direct cost of medical care was $750 million, and the total economic burden about $3.9 billion [3]. In both events, about half of the vaccine produced went unused, to the financial loss of industry and the detriment of the public. Accumulated death and morbidity by repeated outbreaks caused by antigenic variants of these two strains of influenza A virus in successive years exceeded that incurred during the pandemic year. Hence comes the argument for general immunization instead of limited immunization. Morbidity is high in all age groups. Although more frequent at the two ends of the age spectrum (under five and over 65 years), death occurs at all ages. This pattern can be seen throughout the decade of prevalence of a new influenza A virus strain and was evident for A Victoria influenza last winter. The National Institute of Allergy and Infectious Diseases (NIAID) recognized that pandemic influenza A could again be expected in the late 1970s and financed a series of workshops to bring information up to date and consider action that might be taken. Eight workshops were held between 1971 and 1975, and summaries of these have been published [4-11]. The history of failure of the two previous national programs, conducted through conventional channels, to reach a majority of the public and recent consideration of the problems related to another pandemic provide a background for the events related to the current decision for a national program. The threat involved an epidemic of influenza at Fort Dix, N.J., that was due to an influenza A virus in which a double antigenic shift
716
The Decision Process
On February 14, 1976, the Center for Disease Control (CDC) held a meeting involving the NIAID, the Bureau of Biologics of the Food and Drug Administration (BB/FDA), the Department of Defense, Walter Reed Army Institute of Research (WRAIR), and the New Jersey State Health Department Laboratories (NJSHL). On February 13, the CDC had confirmed four isolates from personnel in the Army Basic Combat Training Command at Fort Dix, N.J., as having the HswNI antigenic determinants. Three of these isolates were from individuals with febrile respiratory disease, and one was from a fatal pneumonic case. These isolates had been encountered by the NJSHL among specimens submitted because of high attack rates at Fort Dix. Isolates of the A Victoria influenza strain were made concurrently. The purpose of the meeting was to alert other government agencies and to initiate immediate studies to determine if there was additional evidence of the occurrence of swine-like influenza viruses. On February 20, the BB/FDA, CDC, and NIAID convened an open meeting at the National Institutes of Health (NIH; Bethesda, Md.) that was attended by representatives from the WRAIR and NJSHL; representatives of advisory committees to the BB, CDC, and NIAID, the Armed Forces Epidemiological Board; epidemiologists; virologists; representatives of the pharmaceutical industry; and the press. The purpose was to review the information available to date, to make known the availability of diagnostic reagents, to initiate studies in industry for possible vaccine
production, and to organize rapid research efforts toward determination of the extent and nature of occurrence of "swine" influenza in humans. The data at this time were unequivocal on the occurrence of human-to-human transmission in the outbreak at Fort Dix. After the meeting, staff members of the three agencies held telephone discussions with other scientists who could not attend. On March 10, the CDC convened the Department of Health, Education, and Welfare (DHEW) Committee on Immunization Practices in an open meeting. The following data on swine-type influenza were available and accepted at the meeting. (l) In 1974 a case of swine influenza was diagnosed at the Mayo Clinic (Rochester, Minn.) by viral isolations [12]. (2) In 1975 a case in Sheboygan, Wis., was diagnosed by a rise in antibody level. Unpublished but available data from CDC indicate that there was a history of an outbreak of influenza-like illness in the family of the patient and serologic evidence of infection by swine-type virus. No apparent transmission to school contacts could be identified. (3) The episode at Fort Dix, which occurred between early January and mid-February 1976, yielded five viral isolates; one of these isolates was from a fatal infection. Seven other patients were diagnosed on the basis of increase in level of antibody. The clinical illness in these patients was not distinguishable from illness caused by A Victoria influenza viruses. Further antibody survey revealed that > 500 army personnel were involved in the outbreak (WRAIR and NJSHL, unpublished data). There was seroepidemiologic evidence that one of the patients from Fort Dix may have transmitted the disease to members of his family. (4) Two possible cases of pneumonia in Charlottesville, Va., in late December, were diagnosed by increases in level of antibody. (5) One possible case originated in Clarksdale, Miss. With the exception of the Fort Dix personnel and one of the two Charlottesville patients, the cases had contact with swine with the possibility of swine-to-man transmission. Prior to 1974 there were no documented instances of such transmission, although serologic evidence suggests that it may have occurred to some degree among veterinarians, workers in slaughterhouses, and swine producers [12].
Downloaded from http://jid.oxfordjournals.org/ at Sheffield University on September 7, 2015
(from H3N2 to HswNl) had occurred. Seroepidemiologic data made it clear that individuals who are < 50 years old are basically susceptible to this new variant and that even those > 50 years old who possess antibody may not be immune because of antigenic variance of the 1976 virus from the presumed 1918 virus, as represented by the 1931 isolate from a pig. Although the history of the 1918 pandemic was inevitably raised in the discussions, there was no evidence that the 1976 swine virus was different from other influenza A viruses and thus this was not a major factor in the decision.
Seal, Sencer, and Meyer
News
and Assistant Secretary of Health met with the President to advise him of the problem. On March 24, the President convened a meeting at the White House to review the threat and the recommended course of action. Leading scientists from the academic community and spokesmen for the pharmaceutical industry, the American Medical Association, the American Academy of Family Practice, and the Academy of Pediatrics were invited. After a two-hour discussion during which he was reassured that the threat was real (although not certain), that industry could meet the challenge, and that the medical profession would support the plan, the President gave his approval. On March 25, the CDC, BB/FDA, and NIAID convened another open meeting at the NIH to inform other members of the scientific and industrial communities of the decision and to initiate plans for the necessary testing of vaccines in various segments of the population to determine the dosage requirements and to generate data on reactions to the different vaccines at various dosage levels. On April 2, the CDC convened a meeting of state health departments and medical societies with representatives from all 50 states. The status of the program was reviewed and discussed as were the CDC plans for implementation of the program as the vaccine becomes available. On April 15, the President signed a supplemental appropriation bill to provide $135 million for the recommended national immunization program. The appropriation followed four open hearings in the Congress on the problem, the program, and the use of the funds being requested. On this same date, another open meeting was convened at the NIH to review plans for testing of vaccines in adults and to formulate plans for testing in younger age groups. On April 21, vaccine testing in adults began at the NIH.in volunteers from the DHEW, BB/ FDA, and NIAID. Four pharmaceutical companies are producing vaccines. Two vaccine preparations will be purchased and distributed by DHEW. One type is a monovalent vaccine prepared from aNew Jersey 1976 HswNl isolate for use in the general public.
Downloaded from http://jid.oxfordjournals.org/ at Sheffield University on September 7, 2015
A number of other studies on military posts and in civilian groups had failed to produce any evidence of activity of an influenza virus with swine antigenic characteristics during the winter months of 1975-1976. A Victoria influenza had been prevalent nationwide. The finding of antibody to the swine influenza viruses in younger individuals or even the occurrence of rises in level of antibody to these viruses in cases of illness had to be discounted because of the observation that a small percentage of individuals from whom A Victoria influenza virus was isolated or who had been vaccinated with the H3N2 strains had increases in level of antibody to the swine viruses. Various options of action on the part of the U.S. Public Health Service were discussed after the conclusion was reached that additional data would probably not become available in the immediate future because of the seasonal downturn in respiratory virus activity. These options ranged trom maintaining surveillance only or incorporating the swine strain into the customary vaccine program for high-risk groups to instituting vaccination programs aimed only at schoolchildren and high-risk individuals. One after the other, proposed options were discarded in favor of a program to make vaccine available to the entire public. On March 15, the directors of the CDC, BB/ FDA, and NIAID met with members of the staff of the Assistant Secretary for Health (DHEW), the Comptroller (DHEW), the Commissioner (FDA), and the staff of the Office of Management and Budget of the White House to review the data, the options available, and the reasoning behind the recommended option of having the federal government buy and distribute the vaccine in sufficient quantity for all Americans and of providing funds for the CDC to assist state and local health authorities in organizing the administration of the vaccine. Also, the need was stressed for an urgent decision and action to obtain the needed funds from the Congress if the vaccine was to be produced and distributed in time to make a difference in attack rate if a pandemic began in the fall. After the decision of the Secretary of DHEW to recommend this course of action, the Secretary
717
718
children can be immunized with an adequate dose. All data will be reviewed in open meetings at the NIH before recommendations are made. About 5,000 persons will participate in this testing program. The ability to carry it out quickly stems from the fact that the CDC, BB/FDA, and, more particularly, the NIAID have been engaged for a number of years in research on influenza and other respiratory virus vaccines. This research has developed associations with investigators who are experienced in such studies and who have access to well-defined population groups. These investigators have generously pooled their efforts and have agreed to work from common protocols to meet the urgent needs for data on the vaccines. The U.S. Army is also participating in the testing program in cooperation with the DHEW. The NIAID is planning studies in well-defined population groups to evaluate the effectiveness of the vaccines being used in the national program. The Institute also hopes to be able to evaluate experimental vaccines in comparison with those being commercially supplied. Expanded research on ecology, including further studies on swine-tohuman transmission, is also being implemented. This unprecedented effort to immunize a large majority of the population against influenza will at the very least provide an opportunity to learn how well the voluntary efforts of the medical profession and citizenry can meet the challenge of pandemic influenza, given the availability of an effective vaccine. It can also lead the way to better acceptance and usage of the present vaccines in interpandemic years. What is now needed are better vaccines that can be more quickly produced and that can be more safely given to younger children. Finally, it should be reiterated that the decision of the government was mainly to procure and to distribute the vaccine and to assist in organization of efforts for its use. Recommendations as to usage of the vaccine will be based on data derived by testing in large numbers of people. Decisions on use will be made by those responsible for its administration. Success of the program will depend on the understanding of the medical profession as to the reasons for the program and on the ability to gain the interest and confidence of the public at large that the vaccine is safe and will benefit the recipient in reducing the probability of
Downloaded from http://jid.oxfordjournals.org/ at Sheffield University on September 7, 2015
Also, a more limited quantity of a bivalent vaccine containing the HswN1 1976 viral antigen and the A Victoria H3N2 1975 strain will be available for the high-risk subjects of all ages (i.e., individuals with heart, pulmonary, and renal disease, asthma, or other disabilities, plus those aged 65 and over). Each manufacturer's monovalent vaccine will be tested at three dosage levels, 200, 400, and 800 chick-cell agglutinating (CCA) units, in subjects between the ages of 12 and 50 years. Children between the ages of six and 10 years will be tested with doses of 100, 200, and 400 CCA units after reaction data from adults have been assessed. Younger children will be tested cautiously with sequentially increasing doses beginning at 50 CCA units only after reaction data become available from the older children. Only after tests are completed in children between the ages of three and five years will any plan be considered to test the vaccine in children less than three years old. Bivalent vaccines are being tested at two dosage levels in adult high-risk and normal groups, and smaller doses will be tested cautiously in high-risk subjects at a younger age level as results on reactions and antibody responses become available from the older groups. Concurrent immunization with a monovalent influenza B vaccine is also being tested in some of the subjects receiving the bivalent vaccine. All requirements for informed consent, institutional review, and review by the sponsoring agency are being met in all testing. Subjects receiving placebo or suboptimal doses of vaccine will be offered reimmunization with optimal doses before autumn. Data from the adult tests of monovalent and bivalent vaccines are expected to be available by June 21 and to enable a decision on the recommended dose needed before vaccines can be packaged, released, and in distribution by July. Data on children will be available to allow recommendations for usage at ages below 12 years before schools open in the fall. The testing is expected to provide antibody data enabling determination of the minimal dose that provides a protective level of antibody to a majority of recipients and also data on the nature and frequency of local and systemic reactions that may accompany that particular dose of each manufacturer's vaccine. The reaction data in children will be especially critical in determining whether
Seal, Sencer, and Meyer
719
News
disabling illness and death should influenza again be pandemic. JOHN R. SEAL National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland
DAVID J. SENCER Center for Disease Control A tlanta, Georgia
References 1. Murray, R Some problems in the standardization and control of influenza vaccine in 1957. Am. Rev. Resp. Dis. 83: 160-167, 1961. 2. Dauer, C. c., Serfling, R. E. Mortality from influenza, 1957-58 and 1959-60. Am. Rev. Resp. Dis. 83:15-28,1969. 3. Kavet, J. Influenza and public health. Master's thesis. Harvard School of Public Health, Boston, 1972. 4. Kilbourne, E. D., Chopp in, P. W., Schulze, I. T., Scholtissek, C., Bucher, D. L. Influenza virus polypeptides and antigens-summary of Influenza Workshop I. J. Infect. Dis. 125:447-455, 1972.
Addendum Since the above news article was written, the following additional information has been released. Data on 5,200 adults and children tested thus far with the swine influenza A vaccine were presented at the morning session of the joint meeting of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH), the Bureau of Biologics of the Food and Drug Administration (BB/FDA), the Center for Disease Control (CDC) , and the Department of Defense on Monday, June 21, 1976 at the NIH. Monovalent influenza A/NJ virus vaccine containing 200, 400, or 800 chick cell-agglutinating (CCA) units of viral antigen or placebo was given to 1,920 persons aged 17 years or older. Of these persons, preexisting antibodies to influenza A/NJ
virus were present in 6% of 17- to 23-year-olds, 14% of 24- to 34-year-olds, 25% of 35- to 51year-oIds, and 94% of persons aged 52 years or older. Among persons without preexisting antibodies, 200 and 400 CCA units of split vaccine (Wyeth Laboratories, Philadelphia, Pa. and Parke, Davis and Co., Detroit, Mich.) produced 62%-76% seroconversion, and 200-400 CCA units of whole vaccine (Merrell-National Laboratories, Cincinnati, Ohio and Merck Sharpe and Dohme, West Point, Pa.) produced 70%-96% seroconversion. Among persons with preexisting antibodies, all vaccines produced 73%-87% seroconversion with 200, 400, and 800 CCA units of viral antigen. Analysis indicated that persons born since 1957 (aged 17-23 years) (sic) had lower antibody
Downloaded from http://jid.oxfordjournals.org/ at Sheffield University on September 7, 2015
HARRY M. MEYER, JR. Bureau of Biologics Food and Drug Administration Bethesda, Maryland
5. Kilbourne, E. D., Coleman, M., Choppin, P. W., Dowdle, W. R, Schild, G. C., Schulman, J. L. Immunologic methodology in influenza diagnosis and research-summary of Influenza Workshop II. J. Infect. Dis. 126:219-230, 1972. 6. Kilbourne, E. D., Butler, W. T., Rossen, R D. Specific immunity in influenza-summary of Influenza Workshop III. J. Infect. Dis. 127:220-236, 1973. 7. Fox, J. P., Kilbourne, E. D. Epidemiology of influenza-summary of Influenza Workshop IV. J. Infect. Dis. 128:361-386, 1973. 8. Kilbourne, E. D., Chanock, R M., Choppin, P. W., Davenport, F. M., Fox, J. P., Gregg, M. B., Jackson, G. G., Parkman, P. D. Influenza vaccinessummary of Influenza Workshop V. J. Infect. Dis. 129:750-771, 1974. 9. Easterday, B. C., Couch, R B. Animal influenza: its significance in human infection-summary of Influenza Workshop VI. J. Infect. Dis. 131:602-612, 1975. 10. Choppin, P. W., Kilbourne, E. D., Dowdle, W., Hirst, G. K., JokIik, W. K., Simpson, R. W., White, D. O. Genetics, replication, and inhibition of replication of influenza virus-summary of Influenza Workshop VII. J. Infect. Dis. 132:713723, 1975. 11. Couch, R B., Jackson, G. G. Antivirals in influenza -summary of Influenza Workshop VIII. J. Infect. Dis., 1976 (in press). 12. Smith, T. F., Burgert, E. 0., Jr., Dowdle, W. R, Noble, G. R, Campbell, R., Van Scoy, R. E. Isolation of swine influenza virus from autopsy lung tissue in man. N. Engl. J. Med. 294: 708710, 1976.
720
(bronchospastic) reaction only occurred 6 hr after vaccination, and the subject responded to epinephrine. Administration of 200 or 400 CCA units of whole vaccine to children six to 10 years old resulted in titers of antibody of ~ 1 :20 in 69 %100% of the recipients. Administration of a single dose of 200-400 CCA units of split vaccine to children in this age group resulted in titers of antibody of ~ 1:20 in 5 % -23 % of recipients and also resulted in two- to fivefold fewer systemic side effects. Whole-virus vaccines are more effective as primary immunizing antigens and are more reactogenic than split vaccines. In nearly all adults, a single dose of 200-400 CCA units of vaccine should be adequate to produce presumably protective antibodies in most recipients, with few side effects. Whole and split vaccines appear to be equivalent.
Downloaded from http://jid.oxfordjournals.org/ at Sheffield University on September 7, 2015
responses to influenza A/NJ virus vaccine, particularly to the split-product vaccine. In the 481 subjects in this age group tested, 400 CCA units of whole vaccine produced 75%-96% seroconversion and 400 CCA units of split vaccine produced 32%-64% seroconversion. Persons aged 24 years or older had adequate antibody responses of ~71 % to all vaccines given. Febrile reactions (temperature, ~ 100 F) in adults were found in 1.7% of subjects given placebo, in 0.6%-4.0% of subjects receiving 200 or 400 CCA units of vaccine (value not significantly different from that in controls), and in 3%-12.8% of subjects receiving 800 CCA units of vaccine (value significantly different from that in controls). Reactions were significantly greater than those in controls only in subjects receiving 800 CCA units of the Merck Sharpe and Dohme whole-virus vaccine ( 12.8 % ). One allergic
Seal, Sencer, and Meyer
JUNE 1976
From the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the Center for Disease Control, and the Bureau of Biologics of the Food and Drug Administration A Status Report on National Immunization against Influenza It is important that the medical profession know and understand the course of events related to national immunization against influenza since such events will certainly recur whenever the nation is threatened with pandemic influenza. Memory is short, and it is worth saying that this is the third, not the first, national program to immunize the public or at least a large segment of it against the threat of a pandemic. Lessons gleaned from the inadequacies of the earlier efforts were influential in the current decisions. Basis for Decision
In 1957, when the Asian (H2N2) influenza virus emerged in the Far East, it was recognized as a double antigenic shift (from HINl). The U.S. Public Health Service in cooperation with State and Territorial Health Officers and the pharmaceutical industry initiated a program to immunize the public with a monovalent vaccine. Again in 1968, when the Hong Kong A Strain (H3N2) emerged, a similar decision was made. In both events, vaccine distribution and administration was left to the private sector with the federal government only making recommendations to industry, health officials, and the public. Both efforts must be regarded as failures insofar as the public at large is concerned. In 1957, vaccine production began in June; by mid-November 48.8 million doses of vaccine had been distributed [1]. Unfortunately, the highly visible impact of the epidemic as represented by school closings, industrial absenteeism, and a shortage of hospital beds occurred between September and early November, and demands for the vaccine
Please address requests for reprints to Dr. John R. Seal, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20014.
715
Downloaded from http://jid.oxfordjournals.org/ at Sheffield University on September 7, 2015
ended shortly afterward. Yet more than a third of the estimated 60,000 deaths attributed to that pandemic in the United States occurred between January and March 1958. Another 20,000 deaths occurred in 1960; this number might have been reduced had the still susceptible population been immunologically introduced to the virus by a killed vaccine instead of a live wild virus [2]. The experience of 1968-1969, was similar although less dramatic (30,000 deaths vs. 60,000 in 1957-1958), but an estimated 51 million Americans were ill, the direct cost of medical care was $750 million, and the total economic burden about $3.9 billion [3]. In both events, about half of the vaccine produced went unused, to the financial loss of industry and the detriment of the public. Accumulated death and morbidity by repeated outbreaks caused by antigenic variants of these two strains of influenza A virus in successive years exceeded that incurred during the pandemic year. Hence comes the argument for general immunization instead of limited immunization. Morbidity is high in all age groups. Although more frequent at the two ends of the age spectrum (under five and over 65 years), death occurs at all ages. This pattern can be seen throughout the decade of prevalence of a new influenza A virus strain and was evident for A Victoria influenza last winter. The National Institute of Allergy and Infectious Diseases (NIAID) recognized that pandemic influenza A could again be expected in the late 1970s and financed a series of workshops to bring information up to date and consider action that might be taken. Eight workshops were held between 1971 and 1975, and summaries of these have been published [4-11]. The history of failure of the two previous national programs, conducted through conventional channels, to reach a majority of the public and recent consideration of the problems related to another pandemic provide a background for the events related to the current decision for a national program. The threat involved an epidemic of influenza at Fort Dix, N.J., that was due to an influenza A virus in which a double antigenic shift
716
The Decision Process
On February 14, 1976, the Center for Disease Control (CDC) held a meeting involving the NIAID, the Bureau of Biologics of the Food and Drug Administration (BB/FDA), the Department of Defense, Walter Reed Army Institute of Research (WRAIR), and the New Jersey State Health Department Laboratories (NJSHL). On February 13, the CDC had confirmed four isolates from personnel in the Army Basic Combat Training Command at Fort Dix, N.J., as having the HswNI antigenic determinants. Three of these isolates were from individuals with febrile respiratory disease, and one was from a fatal pneumonic case. These isolates had been encountered by the NJSHL among specimens submitted because of high attack rates at Fort Dix. Isolates of the A Victoria influenza strain were made concurrently. The purpose of the meeting was to alert other government agencies and to initiate immediate studies to determine if there was additional evidence of the occurrence of swine-like influenza viruses. On February 20, the BB/FDA, CDC, and NIAID convened an open meeting at the National Institutes of Health (NIH; Bethesda, Md.) that was attended by representatives from the WRAIR and NJSHL; representatives of advisory committees to the BB, CDC, and NIAID, the Armed Forces Epidemiological Board; epidemiologists; virologists; representatives of the pharmaceutical industry; and the press. The purpose was to review the information available to date, to make known the availability of diagnostic reagents, to initiate studies in industry for possible vaccine
production, and to organize rapid research efforts toward determination of the extent and nature of occurrence of "swine" influenza in humans. The data at this time were unequivocal on the occurrence of human-to-human transmission in the outbreak at Fort Dix. After the meeting, staff members of the three agencies held telephone discussions with other scientists who could not attend. On March 10, the CDC convened the Department of Health, Education, and Welfare (DHEW) Committee on Immunization Practices in an open meeting. The following data on swine-type influenza were available and accepted at the meeting. (l) In 1974 a case of swine influenza was diagnosed at the Mayo Clinic (Rochester, Minn.) by viral isolations [12]. (2) In 1975 a case in Sheboygan, Wis., was diagnosed by a rise in antibody level. Unpublished but available data from CDC indicate that there was a history of an outbreak of influenza-like illness in the family of the patient and serologic evidence of infection by swine-type virus. No apparent transmission to school contacts could be identified. (3) The episode at Fort Dix, which occurred between early January and mid-February 1976, yielded five viral isolates; one of these isolates was from a fatal infection. Seven other patients were diagnosed on the basis of increase in level of antibody. The clinical illness in these patients was not distinguishable from illness caused by A Victoria influenza viruses. Further antibody survey revealed that > 500 army personnel were involved in the outbreak (WRAIR and NJSHL, unpublished data). There was seroepidemiologic evidence that one of the patients from Fort Dix may have transmitted the disease to members of his family. (4) Two possible cases of pneumonia in Charlottesville, Va., in late December, were diagnosed by increases in level of antibody. (5) One possible case originated in Clarksdale, Miss. With the exception of the Fort Dix personnel and one of the two Charlottesville patients, the cases had contact with swine with the possibility of swine-to-man transmission. Prior to 1974 there were no documented instances of such transmission, although serologic evidence suggests that it may have occurred to some degree among veterinarians, workers in slaughterhouses, and swine producers [12].
Downloaded from http://jid.oxfordjournals.org/ at Sheffield University on September 7, 2015
(from H3N2 to HswNl) had occurred. Seroepidemiologic data made it clear that individuals who are < 50 years old are basically susceptible to this new variant and that even those > 50 years old who possess antibody may not be immune because of antigenic variance of the 1976 virus from the presumed 1918 virus, as represented by the 1931 isolate from a pig. Although the history of the 1918 pandemic was inevitably raised in the discussions, there was no evidence that the 1976 swine virus was different from other influenza A viruses and thus this was not a major factor in the decision.
Seal, Sencer, and Meyer
News
and Assistant Secretary of Health met with the President to advise him of the problem. On March 24, the President convened a meeting at the White House to review the threat and the recommended course of action. Leading scientists from the academic community and spokesmen for the pharmaceutical industry, the American Medical Association, the American Academy of Family Practice, and the Academy of Pediatrics were invited. After a two-hour discussion during which he was reassured that the threat was real (although not certain), that industry could meet the challenge, and that the medical profession would support the plan, the President gave his approval. On March 25, the CDC, BB/FDA, and NIAID convened another open meeting at the NIH to inform other members of the scientific and industrial communities of the decision and to initiate plans for the necessary testing of vaccines in various segments of the population to determine the dosage requirements and to generate data on reactions to the different vaccines at various dosage levels. On April 2, the CDC convened a meeting of state health departments and medical societies with representatives from all 50 states. The status of the program was reviewed and discussed as were the CDC plans for implementation of the program as the vaccine becomes available. On April 15, the President signed a supplemental appropriation bill to provide $135 million for the recommended national immunization program. The appropriation followed four open hearings in the Congress on the problem, the program, and the use of the funds being requested. On this same date, another open meeting was convened at the NIH to review plans for testing of vaccines in adults and to formulate plans for testing in younger age groups. On April 21, vaccine testing in adults began at the NIH.in volunteers from the DHEW, BB/ FDA, and NIAID. Four pharmaceutical companies are producing vaccines. Two vaccine preparations will be purchased and distributed by DHEW. One type is a monovalent vaccine prepared from aNew Jersey 1976 HswNl isolate for use in the general public.
Downloaded from http://jid.oxfordjournals.org/ at Sheffield University on September 7, 2015
A number of other studies on military posts and in civilian groups had failed to produce any evidence of activity of an influenza virus with swine antigenic characteristics during the winter months of 1975-1976. A Victoria influenza had been prevalent nationwide. The finding of antibody to the swine influenza viruses in younger individuals or even the occurrence of rises in level of antibody to these viruses in cases of illness had to be discounted because of the observation that a small percentage of individuals from whom A Victoria influenza virus was isolated or who had been vaccinated with the H3N2 strains had increases in level of antibody to the swine viruses. Various options of action on the part of the U.S. Public Health Service were discussed after the conclusion was reached that additional data would probably not become available in the immediate future because of the seasonal downturn in respiratory virus activity. These options ranged trom maintaining surveillance only or incorporating the swine strain into the customary vaccine program for high-risk groups to instituting vaccination programs aimed only at schoolchildren and high-risk individuals. One after the other, proposed options were discarded in favor of a program to make vaccine available to the entire public. On March 15, the directors of the CDC, BB/ FDA, and NIAID met with members of the staff of the Assistant Secretary for Health (DHEW), the Comptroller (DHEW), the Commissioner (FDA), and the staff of the Office of Management and Budget of the White House to review the data, the options available, and the reasoning behind the recommended option of having the federal government buy and distribute the vaccine in sufficient quantity for all Americans and of providing funds for the CDC to assist state and local health authorities in organizing the administration of the vaccine. Also, the need was stressed for an urgent decision and action to obtain the needed funds from the Congress if the vaccine was to be produced and distributed in time to make a difference in attack rate if a pandemic began in the fall. After the decision of the Secretary of DHEW to recommend this course of action, the Secretary
717
718
children can be immunized with an adequate dose. All data will be reviewed in open meetings at the NIH before recommendations are made. About 5,000 persons will participate in this testing program. The ability to carry it out quickly stems from the fact that the CDC, BB/FDA, and, more particularly, the NIAID have been engaged for a number of years in research on influenza and other respiratory virus vaccines. This research has developed associations with investigators who are experienced in such studies and who have access to well-defined population groups. These investigators have generously pooled their efforts and have agreed to work from common protocols to meet the urgent needs for data on the vaccines. The U.S. Army is also participating in the testing program in cooperation with the DHEW. The NIAID is planning studies in well-defined population groups to evaluate the effectiveness of the vaccines being used in the national program. The Institute also hopes to be able to evaluate experimental vaccines in comparison with those being commercially supplied. Expanded research on ecology, including further studies on swine-tohuman transmission, is also being implemented. This unprecedented effort to immunize a large majority of the population against influenza will at the very least provide an opportunity to learn how well the voluntary efforts of the medical profession and citizenry can meet the challenge of pandemic influenza, given the availability of an effective vaccine. It can also lead the way to better acceptance and usage of the present vaccines in interpandemic years. What is now needed are better vaccines that can be more quickly produced and that can be more safely given to younger children. Finally, it should be reiterated that the decision of the government was mainly to procure and to distribute the vaccine and to assist in organization of efforts for its use. Recommendations as to usage of the vaccine will be based on data derived by testing in large numbers of people. Decisions on use will be made by those responsible for its administration. Success of the program will depend on the understanding of the medical profession as to the reasons for the program and on the ability to gain the interest and confidence of the public at large that the vaccine is safe and will benefit the recipient in reducing the probability of
Downloaded from http://jid.oxfordjournals.org/ at Sheffield University on September 7, 2015
Also, a more limited quantity of a bivalent vaccine containing the HswN1 1976 viral antigen and the A Victoria H3N2 1975 strain will be available for the high-risk subjects of all ages (i.e., individuals with heart, pulmonary, and renal disease, asthma, or other disabilities, plus those aged 65 and over). Each manufacturer's monovalent vaccine will be tested at three dosage levels, 200, 400, and 800 chick-cell agglutinating (CCA) units, in subjects between the ages of 12 and 50 years. Children between the ages of six and 10 years will be tested with doses of 100, 200, and 400 CCA units after reaction data from adults have been assessed. Younger children will be tested cautiously with sequentially increasing doses beginning at 50 CCA units only after reaction data become available from the older children. Only after tests are completed in children between the ages of three and five years will any plan be considered to test the vaccine in children less than three years old. Bivalent vaccines are being tested at two dosage levels in adult high-risk and normal groups, and smaller doses will be tested cautiously in high-risk subjects at a younger age level as results on reactions and antibody responses become available from the older groups. Concurrent immunization with a monovalent influenza B vaccine is also being tested in some of the subjects receiving the bivalent vaccine. All requirements for informed consent, institutional review, and review by the sponsoring agency are being met in all testing. Subjects receiving placebo or suboptimal doses of vaccine will be offered reimmunization with optimal doses before autumn. Data from the adult tests of monovalent and bivalent vaccines are expected to be available by June 21 and to enable a decision on the recommended dose needed before vaccines can be packaged, released, and in distribution by July. Data on children will be available to allow recommendations for usage at ages below 12 years before schools open in the fall. The testing is expected to provide antibody data enabling determination of the minimal dose that provides a protective level of antibody to a majority of recipients and also data on the nature and frequency of local and systemic reactions that may accompany that particular dose of each manufacturer's vaccine. The reaction data in children will be especially critical in determining whether
Seal, Sencer, and Meyer
719
News
disabling illness and death should influenza again be pandemic. JOHN R. SEAL National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland
DAVID J. SENCER Center for Disease Control A tlanta, Georgia
References 1. Murray, R Some problems in the standardization and control of influenza vaccine in 1957. Am. Rev. Resp. Dis. 83: 160-167, 1961. 2. Dauer, C. c., Serfling, R. E. Mortality from influenza, 1957-58 and 1959-60. Am. Rev. Resp. Dis. 83:15-28,1969. 3. Kavet, J. Influenza and public health. Master's thesis. Harvard School of Public Health, Boston, 1972. 4. Kilbourne, E. D., Chopp in, P. W., Schulze, I. T., Scholtissek, C., Bucher, D. L. Influenza virus polypeptides and antigens-summary of Influenza Workshop I. J. Infect. Dis. 125:447-455, 1972.
Addendum Since the above news article was written, the following additional information has been released. Data on 5,200 adults and children tested thus far with the swine influenza A vaccine were presented at the morning session of the joint meeting of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH), the Bureau of Biologics of the Food and Drug Administration (BB/FDA), the Center for Disease Control (CDC) , and the Department of Defense on Monday, June 21, 1976 at the NIH. Monovalent influenza A/NJ virus vaccine containing 200, 400, or 800 chick cell-agglutinating (CCA) units of viral antigen or placebo was given to 1,920 persons aged 17 years or older. Of these persons, preexisting antibodies to influenza A/NJ
virus were present in 6% of 17- to 23-year-olds, 14% of 24- to 34-year-olds, 25% of 35- to 51year-oIds, and 94% of persons aged 52 years or older. Among persons without preexisting antibodies, 200 and 400 CCA units of split vaccine (Wyeth Laboratories, Philadelphia, Pa. and Parke, Davis and Co., Detroit, Mich.) produced 62%-76% seroconversion, and 200-400 CCA units of whole vaccine (Merrell-National Laboratories, Cincinnati, Ohio and Merck Sharpe and Dohme, West Point, Pa.) produced 70%-96% seroconversion. Among persons with preexisting antibodies, all vaccines produced 73%-87% seroconversion with 200, 400, and 800 CCA units of viral antigen. Analysis indicated that persons born since 1957 (aged 17-23 years) (sic) had lower antibody
Downloaded from http://jid.oxfordjournals.org/ at Sheffield University on September 7, 2015
HARRY M. MEYER, JR. Bureau of Biologics Food and Drug Administration Bethesda, Maryland
5. Kilbourne, E. D., Coleman, M., Choppin, P. W., Dowdle, W. R, Schild, G. C., Schulman, J. L. Immunologic methodology in influenza diagnosis and research-summary of Influenza Workshop II. J. Infect. Dis. 126:219-230, 1972. 6. Kilbourne, E. D., Butler, W. T., Rossen, R D. Specific immunity in influenza-summary of Influenza Workshop III. J. Infect. Dis. 127:220-236, 1973. 7. Fox, J. P., Kilbourne, E. D. Epidemiology of influenza-summary of Influenza Workshop IV. J. Infect. Dis. 128:361-386, 1973. 8. Kilbourne, E. D., Chanock, R M., Choppin, P. W., Davenport, F. M., Fox, J. P., Gregg, M. B., Jackson, G. G., Parkman, P. D. Influenza vaccinessummary of Influenza Workshop V. J. Infect. Dis. 129:750-771, 1974. 9. Easterday, B. C., Couch, R B. Animal influenza: its significance in human infection-summary of Influenza Workshop VI. J. Infect. Dis. 131:602-612, 1975. 10. Choppin, P. W., Kilbourne, E. D., Dowdle, W., Hirst, G. K., JokIik, W. K., Simpson, R. W., White, D. O. Genetics, replication, and inhibition of replication of influenza virus-summary of Influenza Workshop VII. J. Infect. Dis. 132:713723, 1975. 11. Couch, R B., Jackson, G. G. Antivirals in influenza -summary of Influenza Workshop VIII. J. Infect. Dis., 1976 (in press). 12. Smith, T. F., Burgert, E. 0., Jr., Dowdle, W. R, Noble, G. R, Campbell, R., Van Scoy, R. E. Isolation of swine influenza virus from autopsy lung tissue in man. N. Engl. J. Med. 294: 708710, 1976.
720
(bronchospastic) reaction only occurred 6 hr after vaccination, and the subject responded to epinephrine. Administration of 200 or 400 CCA units of whole vaccine to children six to 10 years old resulted in titers of antibody of ~ 1 :20 in 69 %100% of the recipients. Administration of a single dose of 200-400 CCA units of split vaccine to children in this age group resulted in titers of antibody of ~ 1:20 in 5 % -23 % of recipients and also resulted in two- to fivefold fewer systemic side effects. Whole-virus vaccines are more effective as primary immunizing antigens and are more reactogenic than split vaccines. In nearly all adults, a single dose of 200-400 CCA units of vaccine should be adequate to produce presumably protective antibodies in most recipients, with few side effects. Whole and split vaccines appear to be equivalent.
Downloaded from http://jid.oxfordjournals.org/ at Sheffield University on September 7, 2015
responses to influenza A/NJ virus vaccine, particularly to the split-product vaccine. In the 481 subjects in this age group tested, 400 CCA units of whole vaccine produced 75%-96% seroconversion and 400 CCA units of split vaccine produced 32%-64% seroconversion. Persons aged 24 years or older had adequate antibody responses of ~71 % to all vaccines given. Febrile reactions (temperature, ~ 100 F) in adults were found in 1.7% of subjects given placebo, in 0.6%-4.0% of subjects receiving 200 or 400 CCA units of vaccine (value not significantly different from that in controls), and in 3%-12.8% of subjects receiving 800 CCA units of vaccine (value significantly different from that in controls). Reactions were significantly greater than those in controls only in subjects receiving 800 CCA units of the Merck Sharpe and Dohme whole-virus vaccine ( 12.8 % ). One allergic
Seal, Sencer, and Meyer
