THE JOUR:\iAL OF INFECTIOUS DISEASE. VOL. 136, SUPPLDIE;O\T • DECDIBER 1977 © 1977 by the University of Chicago. All rights reserved.
Age-Related Heterologous Antibody Responses to Influenza Virus Vaccination Gary R. Noble, Harold S. Kaye, Alan P. Kendal, and Walter R. Dowdle
From the World Health Organization Collaborating Center for Influenza, Respiratory Virology Branch, Virology Division, Bureau of Laboratories, Center for Disease Control, Atlanta, Georgia
Francis observed that persons who have an initial infection caused by one strain of influenza virus and are subsequently infected by strains antigenically related to the initial strain frequently form high titers of HAl antibody to the strain that caused the initial infection. This observation led him to propose the doctrine of original antigenic sin [1]. The 1976 National Influenza Immunization Field Trials involving populations of all ages provided an opportunity to examine the heterologous HAl antibody responses to HswlNI and H3N2 viral antigens. Vaccination with influenza A/New Jersey /76 (Hsw 1N I) virus produced a high rate of antibody response to influenza A/PR/8/34 (HOUse of trade names is for identification only and does not constitute endorsement by the u.s. Public Health Service or by the U.S. Department of Health, Education, and Welfare. We acknowledge the technical assistance of B. K. Fiedler, Beverly C. Lawrence, Joanne L. Patton, Carol J. Reed, C. H. Ring, and W. B. Yarbrough. Please address requests for reprints to Dr. Gary R. Noble, Respiratory Virology Branch 7·H2, Center for Disease Control, Atlanta, Georgia 30333.
Nl) and A/FM/l/47 (HINl) viruses in persons whose first infections had been with these or closely related strains. HONI and HlNl strains are known to share common antigenic determinants with Hswl hemagglutinins [2]. Vaccination with A/New Jersey /76 virus produced only low levels of antibody to influenza A/Japan/305/57 (H2N2) and A/Victoria/3/75 (H3N2) virus strains, and these responses were less clearly related to primary infections. Vaccination or infection with H3N2 strains produced a low frequency of increases in levels of HAl antibody to A/New Jersey /76 virus. Materials and Methods
Viruses. Reference strains of influenza virus AjPRj8/34 (HONl), A/FM/lj47 (HlNl), AIJapan/305j57 (H2N2), and A/Victoria! 3/75 (H3N2) were from the collection of the World Health Organization (WHO) Collaborating Center for Influenza, Center for Disease Control (CDC), Atlanta, Ga. Influenza A/New Jersey I 8/76 (Hsw 1N 1) virus was grown from the isolate provided by the New Jersey State Department of Health [3].
8686
Downloaded from http://jid.oxfordjournals.org/ at Boston University on August 3, 2015
Heterologous hemagglutination-inhibiting (HAl) antibody responses to influenza A/New Jerseyj76 (HswlNl) virus vaccine were examined in individuals receiving doses of 200, 400, or 800 chick cell-agglutinating units of whole-virus or split-virus products during the 1976 National Influenza Vaccine Test Program. Vaccination with influenza A/New Jersey /76 virus produced a high rate or' heterologous antibody response to influenza A/PR/8/34 (HON1) and A/FM/l/47 (HIN1) viruses in persons whose original antigenic experience according to their age was with HON} or HI NI strains, respectively. Vaccination with A/New jersey/76 virus produced only low levels of HAl antibody to influenza A/Japan/305/57 (H2N2) and A/Victoria/3/75 (H3N2) viruses, and these responses were less clearly related to primary infections. Thus the greatest heterologous HAl antibody responses occurred when there were shared antigenic determinants between the hemagglutinins of the vaccine virus and the viruses that had caused the initial priming infection. However, when vaccinations or infections with H3N2 and HswlNI strains may both be occurring in the population, even infrequent formation of heterologous antibody may make it difficult to interpret serologic data precisely.
5687
Age-Related Antibody Responses
Figure 1. Experiences with prototypic or related strains of influenza A virus in five age groups. The populations with primary exposure to the subtypes are shown; highest rates of infection do not occur in the first four to five years of life. A/ Jap/57 = A/Japan/57 virus, and A/HK/68 = A/Hong Kong/68 virus.
whole-virus vaccine contammg influenza A/ England/42/72 virus (700 CCA units) and influenza B/Massachusetts/l/71 virus (300 CCA units), and sera were obtained two weeks later. In the 1975 CDC study, office workers were given one dose of whole-virus vaccine containing influenza A/Port Chalmers/ 1/73 virus (350 CCA units), A/Scotland/840/74 virus (350 CCA units), and B/Hong Kong/5/72 virus (500 CCA units), and sera were drawn three weeks later. Tests for HAl antibody. HAl antibody titers in sera were tested with use of semiautomated microtiter equipment [5]. Classification of subjects by primary exposure to major influenza hemagglutinin subtypes. Subjects were chosen such that groups of persons born during each period of prevalence of a major influenza hemagglutinin subtype could be made (figure I). Since some pre-school children may escape infection with influenza virus until the fourth or fifth year of life, the age groups were chosen to reflect possibly lower rates of infection during the first several years of life preceding the appearance of a major new hemagglutinin subtype.
Results
A/New jersey/76 virus vaccine study. Antibody patterns before vaccination. The distributions of antibody to five prototypic influenza virus strains are shown in table 1. In each of the five age groups shown, the highest prevalence of antibody to prototypic strains before vaccination was found in groups having had a primary experience with these or related strains during their youth. The prevalence of antibody to the initially infecting strains ranged from 48% for AI PR/8/34 virus in persons 35-51 years old to Years of Major Influenza Subtype Prevalence
'30 ±
'18
'25
'47
'42 Year of Birth
'57
'52
'68
'64
Downloaded from http://jid.oxfordjournals.org/ at Boston University on August 3, 2015
Sera. For the examination of heterologous response to A/New Jersey/76 and A/Victoria/ 3/75 virus vaccines, sera were selected from the 1976 vaccine studies; these studies were supported by the U.S. Public Health Service, U.S. Department of Health, Education, and Welfare, or the Department of Defense and coordinated by the following investigators: Dr. R. G. Douglas (University of Rochester, Rochester, N.Y.), Dr. T. Eickhoff (University of Colorado, Denver, Colo.), Dr. J. Gwaltney, Jr. (University of Virginia, Charlottesville, Va.), Dr. S. Lerman (University of Nebraska, Omaha, Nebr.), Dr. M. Levine (University of Maryland, Baltimore, Md.), Dr. K. McIntosh (University of Colorado), and Dr. G. R. Noble (CDC). Sera were obtained three weeks after vaccination from subjects given one dose of monovalent A/New Jersey /76 virus vaccine prepared by Merck Sharp and Dohme (West Point, Pa.; wholevirus vaccine), Merrell-National Laboratories (Cincinnati, Ohio; whole-virus vaccine) or Wyeth Laboratories (Philadelphia, Pa.; split-virus vaccine), or one dose of monovalent A/Victoria/75 virus vaccine prepared by these companies or by Parke, Davis and Company (Detroit, Mich.; splitvirus vaccine). Results of vaccination with 200, 400, and 800 chick cell-agglutinating (CCA) units or lesser doses for children [4] were combined for analysis. The sera examined for heterologous responses after infection with H3N2 viruses were from those received for diagnostic testing by the WHO Collaborating Center for Influenza from J anuary 1975 to March 1976. The sera examined for heterologous responses after vaccination with H3N2 strains were obtained from two studies conducted by the CDC, one in 1974 and a second in 1975. In the 1974 study, residents of a retirement home who were older than 65 years of age were given one dose of commercially available
Noble et al.
S688
Table 1. Prevalence of HAl antibody to prototypic strains of influenza A virus before vaccination. Age (years)
No. tested*
A/NJ/ 76
3-12 13-24 25-34 35-51 ;;;.52
131-137 81-88 87-91 84-85 73-74
0 4 5 11 76
Table 2. Geometric mean titers (GMTs) of antibody to indicated strain of influenza virus before and after vaccination with A/New Jersey (NJ)/76 (HswlNI) virus.
A/PR/ A/FM/ A/Jpn/ A/Vic/ 34 47 57 75 0 1 28 48 30
1 2 66 52 31
9 98 88 77 70
Reciprocal GMTs before/ after vaccination
53 36 23 16 17
Age (years)
No. tested"
3-12 131-137 13-24 81-88 25-34 87-91 35-51 84-85 ;;;'52 73-74
A/PR/ A/FM/ A/lpn/ 34 47 57
5/18 5/5 6/29 5/6 6/123 10/22 7/118 14/54 30/451 10/16
A/Vic/ 75
16/22 5/6 6/7 6/11 123/208 11/12 26/167 62/102 9/12 16/48 40/50 8/10 10/21 24/29 8/9
NOTE. Data are the combined results of vaccination with 200, 400, or 800 chick cell-agglutinating units of vaccine prepared by Merrell-National Laboratories (Cincinnati, Ohio), Merck Sharp and Dohme (West Point, Pa.), and Wyeth Laboratories (Philadelphia, Pa.). See table 1 for definition of viruses. *See footnote to table 1.
98% for A/Japan/305/57 virus in persons 1324 years old. Antibody response after vaccination with A / New Jersey/76 (HswlNl) virus. The magnitude and frequency of homologous and heterologous antibody responses are described in table 2 and in figures 2-5. The highest responses of HAl antibody to A/New Jersey /8/76 virus occurred in persons having had an initial influenza virus infection with Hsw l, HO, or HI hemagglutinin subtypes. Three weeks after vaccination the geometric mean titers (GMTs) were ~I: 118 in the groups older than 24 years, whereas in those aged 24 years and younger, the maximal GMT was 1:29. Fourfold or greater rises in titer of antibody to A/PR/8/34 virus were most frequent (49%) among those 35-51 years of age who had their
initial childhood influenza infections with virus antigenically similar to A/PR/8j34 virus (figure 2). Fourfold or greater rises in titer of antibody to A/PR/8/34 virus occurred in eight of 83 subjects aged 13-24 years. Since seven of these eight subjects were born between 1952 and 1957, the responses to A/PR/8/34 virus may reflect stimulation of antibody to an initially infecting HI strain that cross-reacts with A/PRj8/34 virus. Fourfold or greater rises in titer of HAl antibody to A/FM/I/47 virus were most frequent (71%) in the 25- to 34-year age group, a finding reflecting the original antigenic sin of these individuals (figure 2). The increase in GMT of antibody to A/FMjI /47 virus from I :26 in sera obtained before vaccination to I: 167
100
~A/PR/34 80 IZ
Figure 2. Percentages of persons having fourfold or greater rises in titer of HAl antibody to indicated strain of influenza A virus after one dose (200, 400, or 800 chick cellagglutinating units) of influenza A/ New Jersey(NJ)/76 virus vaccines (provided by Merrell-National Laboratories, Cincinnati, Ohio; Merck Sharp and Dohme, West Point, Pa.; or Wyeth Laboratories, Philadelphia, Pa.).
TA/NJ/76
~ 60 D:: W
a 40 20
312
1324
25-
34
3551
~52
No.TESTED 135
83
89
85
73
AGE (yrs)
3-
1324
25-
12
34
3551
~52
137
81
91
85
73
Downloaded from http://jid.oxfordjournals.org/ at Boston University on August 3, 2015
NOTE. Data are given as the percentages of persons with titers of HAl antibody of ;;;'1:20 to the indicated strain of influenza virus. A/NJ/76 = A/New Jersey/8/76; A/PR/34 = A/PR/8/34; A/FM/47 = A/FM/1/47; A/Jpn/57 = A/Japan/ 305/57; and A/Vic/75 = A/Victoria/3/75. *The numbers of sera used for a comparison of A/Victoria/ 3/75 and A/New Jersey/76 antibody responses were 146, 73, 135, 189, and 69 for those aged three to 12, 13-24, 25-34,35-51, and ;;;'52, respectively (figure 3).
A/NJ/ 76
Age-Related Antibody Responses
5689
100
Figure 3. Percentages of persons having fourfold or greater rises in titer of HAl antibody to indicated strain of influenza A virus after one dose (200, 400, or 800 chick cellagglutinating units) of influenza A/ New Jersey(NJ)/76 virus vaccines (provided by Merrell-National Laboratories, Cincinnati, Ohio; Merck Sharp and Dohme, West Point, Pa.; or Wyeth Laboratories, Philadelphia, Pa.}, A/Jap/57 = A/Japan/57 virus, and A/Vic/7 5 = A/Victoria/ 75 virus.
T
TA/NJ/76
A/NJ/76
.....
z
~ 60 0::: W
a.. 40 20
a
1324
2534
3551
No.TESTED 133
82
90
86
100
312
~52
1324
2534
3551
~52
73
135
189
69
146
73
of rises in titers of antibody to A/New Jersey virus was higher in the three- to 12-year age group, born during the H3N2 virus era (figures I and 3), than in other age groups. Heterologous Hswl antibody responses to infection or vaccination with H3N2 virus. The rate of heterologous Hsw I antibody response to infection with H3N2 viruses was examined in sera collected between January 1975 and March 1976. Of 128 pairs of acute- and convalescent-phase sera exhibiting a fourfold or greater rise in titer of antibody to either A/Port Chalmers/l/73 or A/ Victoria/ 3/75 virus, four (3%) also had a rise in titer of antibody to the Hsw I antigen (table 3). These rises were seen with or without preexisting Hsw I antibody in those older or younger than 50 years. The heterologous Hswl antibody response was II % after vaccination with whole-virus products containing 700 CCA units of influenza A H3N2 A/FM/47
A/PR/34
o
PRE
o
PRE
•
POST
•
POST
80
I-
~60
o
0:::
w
0..40
20
O~=--"""':=
AGE (yrs) 3-12 13-?4 25-34 35-51 No.TESTED 135 83 89 85
~52
73
3-12 13-24 25-34 35-51 137 81 91 85
~52
73
Downloaded from http://jid.oxfordjournals.org/ at Boston University on August 3, 2015
312
AGE (yrs )
in sera obtained after vaccination in this age group also reflects this phenomenon (table 2). The frequencies of fourfold or greater antibody responses to A/Japan/305/57 virus after vaccination with A/New Jersey /76 virus did not differ between the 13- to 24-year age group, which had its primary infection with this strain, and the 25- to 34-year age group (figure 3). Likewise, the ratios of GMTs of antibody to A/Japan / 57 virus in the sera obtained before and after vaccination are similar in these two age groups (table 2). The very high prevalence of antibody to A/Japan/57 virus before vaccination in those 13-24 years old (figure 5) may have dampened the response. The heterologous A/Victoria/3/75 antibody response after vaccination with A/New Jersey / 76 virus was low in all age groups, although the proportion of rises in levels of heterologous antibody to A/Victoria virus to the total number
Figure 4. Percentages of persons with titers of HAl antibody to indicated strain of influenza virus of ~ 1: 40 before and after vaccination with A/New Jersey/76 virus (200, 400, or 800 chick cell-agglutinating units) vaccines (provided by MerrellNational Laboratories, Cincinnati, Ohio; Merck Sharp and Dohme, West Point, Pa; or Wyeth Laboratories, Philadelphia, Pa.).
~A/VIC/75
~A/JAP/57 80
5690
Noble et al.
too
A/JAP/57
A/VIC/75
D
PRE
o
PRE
•
POST
•
POST
80 ~
~ 60
o a:: w a.. 40 20
13-24 25·34 35-51 82 90 86
~52
73
3-12 146
13-24 25-34 35-51 73 135 189
component and 300-500 CCA units of influenza B virus. Rises in titers of heterologous antibody occurred in persons with and without preexisting Hswl antibody, older or younger than 51 years (table 4). When the antibody response to vaccination with A/Victoria/3/75 virus in the 1976 influenza virus vaccine test program was examined, the heterologous Hswl antibody response observed was lower than that in the earlier H3N2 virus vaccine groups. Only two of 174 recipients of vaccine with a rise in titer of antibody to A/ Victoria virus also had a rise in the level of antibody to Hswl (table 4). No rise in titers of antibody to Hswl occurred in recipients of vaccine Table 3. Rises in titers of HAl antibody to influenza virus antigen Hswl among subjects with serologically confirmed infections with influenza A (H3N2) virus.
Age (years) 3-12 13-24 25-34 35-51 ~52
Total
No. tested 5 80 9 13 21 128
No. with fourfold or greater rise in Hsw 1 antibody titer (%)*
2
4 (3)
NOTE. All subjects had fourfold or greater rises in titer of antibody to A/Port Chalmers/l/73 or A/Victoria/3/75 viruses between January 1975 and March 1976. *The ratios of reciprocal antibody titers to A/New Jersey/ 76 virus or A/Mayo Clinic/l03/74 virus before and after vaccination for the four cases were (in order) < 10/20,
Age-Related Heterologous Antibody Responses to Influenza Virus Vaccination Gary R. Noble, Harold S. Kaye, Alan P. Kendal, and Walter R. Dowdle
From the World Health Organization Collaborating Center for Influenza, Respiratory Virology Branch, Virology Division, Bureau of Laboratories, Center for Disease Control, Atlanta, Georgia
Francis observed that persons who have an initial infection caused by one strain of influenza virus and are subsequently infected by strains antigenically related to the initial strain frequently form high titers of HAl antibody to the strain that caused the initial infection. This observation led him to propose the doctrine of original antigenic sin [1]. The 1976 National Influenza Immunization Field Trials involving populations of all ages provided an opportunity to examine the heterologous HAl antibody responses to HswlNI and H3N2 viral antigens. Vaccination with influenza A/New Jersey /76 (Hsw 1N I) virus produced a high rate of antibody response to influenza A/PR/8/34 (HOUse of trade names is for identification only and does not constitute endorsement by the u.s. Public Health Service or by the U.S. Department of Health, Education, and Welfare. We acknowledge the technical assistance of B. K. Fiedler, Beverly C. Lawrence, Joanne L. Patton, Carol J. Reed, C. H. Ring, and W. B. Yarbrough. Please address requests for reprints to Dr. Gary R. Noble, Respiratory Virology Branch 7·H2, Center for Disease Control, Atlanta, Georgia 30333.
Nl) and A/FM/l/47 (HINl) viruses in persons whose first infections had been with these or closely related strains. HONI and HlNl strains are known to share common antigenic determinants with Hswl hemagglutinins [2]. Vaccination with A/New Jersey /76 virus produced only low levels of antibody to influenza A/Japan/305/57 (H2N2) and A/Victoria/3/75 (H3N2) virus strains, and these responses were less clearly related to primary infections. Vaccination or infection with H3N2 strains produced a low frequency of increases in levels of HAl antibody to A/New Jersey /76 virus. Materials and Methods
Viruses. Reference strains of influenza virus AjPRj8/34 (HONl), A/FM/lj47 (HlNl), AIJapan/305j57 (H2N2), and A/Victoria! 3/75 (H3N2) were from the collection of the World Health Organization (WHO) Collaborating Center for Influenza, Center for Disease Control (CDC), Atlanta, Ga. Influenza A/New Jersey I 8/76 (Hsw 1N 1) virus was grown from the isolate provided by the New Jersey State Department of Health [3].
8686
Downloaded from http://jid.oxfordjournals.org/ at Boston University on August 3, 2015
Heterologous hemagglutination-inhibiting (HAl) antibody responses to influenza A/New Jerseyj76 (HswlNl) virus vaccine were examined in individuals receiving doses of 200, 400, or 800 chick cell-agglutinating units of whole-virus or split-virus products during the 1976 National Influenza Vaccine Test Program. Vaccination with influenza A/New Jersey /76 virus produced a high rate or' heterologous antibody response to influenza A/PR/8/34 (HON1) and A/FM/l/47 (HIN1) viruses in persons whose original antigenic experience according to their age was with HON} or HI NI strains, respectively. Vaccination with A/New jersey/76 virus produced only low levels of HAl antibody to influenza A/Japan/305/57 (H2N2) and A/Victoria/3/75 (H3N2) viruses, and these responses were less clearly related to primary infections. Thus the greatest heterologous HAl antibody responses occurred when there were shared antigenic determinants between the hemagglutinins of the vaccine virus and the viruses that had caused the initial priming infection. However, when vaccinations or infections with H3N2 and HswlNI strains may both be occurring in the population, even infrequent formation of heterologous antibody may make it difficult to interpret serologic data precisely.
5687
Age-Related Antibody Responses
Figure 1. Experiences with prototypic or related strains of influenza A virus in five age groups. The populations with primary exposure to the subtypes are shown; highest rates of infection do not occur in the first four to five years of life. A/ Jap/57 = A/Japan/57 virus, and A/HK/68 = A/Hong Kong/68 virus.
whole-virus vaccine contammg influenza A/ England/42/72 virus (700 CCA units) and influenza B/Massachusetts/l/71 virus (300 CCA units), and sera were obtained two weeks later. In the 1975 CDC study, office workers were given one dose of whole-virus vaccine containing influenza A/Port Chalmers/ 1/73 virus (350 CCA units), A/Scotland/840/74 virus (350 CCA units), and B/Hong Kong/5/72 virus (500 CCA units), and sera were drawn three weeks later. Tests for HAl antibody. HAl antibody titers in sera were tested with use of semiautomated microtiter equipment [5]. Classification of subjects by primary exposure to major influenza hemagglutinin subtypes. Subjects were chosen such that groups of persons born during each period of prevalence of a major influenza hemagglutinin subtype could be made (figure I). Since some pre-school children may escape infection with influenza virus until the fourth or fifth year of life, the age groups were chosen to reflect possibly lower rates of infection during the first several years of life preceding the appearance of a major new hemagglutinin subtype.
Results
A/New jersey/76 virus vaccine study. Antibody patterns before vaccination. The distributions of antibody to five prototypic influenza virus strains are shown in table 1. In each of the five age groups shown, the highest prevalence of antibody to prototypic strains before vaccination was found in groups having had a primary experience with these or related strains during their youth. The prevalence of antibody to the initially infecting strains ranged from 48% for AI PR/8/34 virus in persons 35-51 years old to Years of Major Influenza Subtype Prevalence
'30 ±
'18
'25
'47
'42 Year of Birth
'57
'52
'68
'64
Downloaded from http://jid.oxfordjournals.org/ at Boston University on August 3, 2015
Sera. For the examination of heterologous response to A/New Jersey/76 and A/Victoria/ 3/75 virus vaccines, sera were selected from the 1976 vaccine studies; these studies were supported by the U.S. Public Health Service, U.S. Department of Health, Education, and Welfare, or the Department of Defense and coordinated by the following investigators: Dr. R. G. Douglas (University of Rochester, Rochester, N.Y.), Dr. T. Eickhoff (University of Colorado, Denver, Colo.), Dr. J. Gwaltney, Jr. (University of Virginia, Charlottesville, Va.), Dr. S. Lerman (University of Nebraska, Omaha, Nebr.), Dr. M. Levine (University of Maryland, Baltimore, Md.), Dr. K. McIntosh (University of Colorado), and Dr. G. R. Noble (CDC). Sera were obtained three weeks after vaccination from subjects given one dose of monovalent A/New Jersey /76 virus vaccine prepared by Merck Sharp and Dohme (West Point, Pa.; wholevirus vaccine), Merrell-National Laboratories (Cincinnati, Ohio; whole-virus vaccine) or Wyeth Laboratories (Philadelphia, Pa.; split-virus vaccine), or one dose of monovalent A/Victoria/75 virus vaccine prepared by these companies or by Parke, Davis and Company (Detroit, Mich.; splitvirus vaccine). Results of vaccination with 200, 400, and 800 chick cell-agglutinating (CCA) units or lesser doses for children [4] were combined for analysis. The sera examined for heterologous responses after infection with H3N2 viruses were from those received for diagnostic testing by the WHO Collaborating Center for Influenza from J anuary 1975 to March 1976. The sera examined for heterologous responses after vaccination with H3N2 strains were obtained from two studies conducted by the CDC, one in 1974 and a second in 1975. In the 1974 study, residents of a retirement home who were older than 65 years of age were given one dose of commercially available
Noble et al.
S688
Table 1. Prevalence of HAl antibody to prototypic strains of influenza A virus before vaccination. Age (years)
No. tested*
A/NJ/ 76
3-12 13-24 25-34 35-51 ;;;.52
131-137 81-88 87-91 84-85 73-74
0 4 5 11 76
Table 2. Geometric mean titers (GMTs) of antibody to indicated strain of influenza virus before and after vaccination with A/New Jersey (NJ)/76 (HswlNI) virus.
A/PR/ A/FM/ A/Jpn/ A/Vic/ 34 47 57 75 0 1 28 48 30
1 2 66 52 31
9 98 88 77 70
Reciprocal GMTs before/ after vaccination
53 36 23 16 17
Age (years)
No. tested"
3-12 131-137 13-24 81-88 25-34 87-91 35-51 84-85 ;;;'52 73-74
A/PR/ A/FM/ A/lpn/ 34 47 57
5/18 5/5 6/29 5/6 6/123 10/22 7/118 14/54 30/451 10/16
A/Vic/ 75
16/22 5/6 6/7 6/11 123/208 11/12 26/167 62/102 9/12 16/48 40/50 8/10 10/21 24/29 8/9
NOTE. Data are the combined results of vaccination with 200, 400, or 800 chick cell-agglutinating units of vaccine prepared by Merrell-National Laboratories (Cincinnati, Ohio), Merck Sharp and Dohme (West Point, Pa.), and Wyeth Laboratories (Philadelphia, Pa.). See table 1 for definition of viruses. *See footnote to table 1.
98% for A/Japan/305/57 virus in persons 1324 years old. Antibody response after vaccination with A / New Jersey/76 (HswlNl) virus. The magnitude and frequency of homologous and heterologous antibody responses are described in table 2 and in figures 2-5. The highest responses of HAl antibody to A/New Jersey /8/76 virus occurred in persons having had an initial influenza virus infection with Hsw l, HO, or HI hemagglutinin subtypes. Three weeks after vaccination the geometric mean titers (GMTs) were ~I: 118 in the groups older than 24 years, whereas in those aged 24 years and younger, the maximal GMT was 1:29. Fourfold or greater rises in titer of antibody to A/PR/8/34 virus were most frequent (49%) among those 35-51 years of age who had their
initial childhood influenza infections with virus antigenically similar to A/PR/8j34 virus (figure 2). Fourfold or greater rises in titer of antibody to A/PR/8/34 virus occurred in eight of 83 subjects aged 13-24 years. Since seven of these eight subjects were born between 1952 and 1957, the responses to A/PR/8/34 virus may reflect stimulation of antibody to an initially infecting HI strain that cross-reacts with A/PRj8/34 virus. Fourfold or greater rises in titer of HAl antibody to A/FM/I/47 virus were most frequent (71%) in the 25- to 34-year age group, a finding reflecting the original antigenic sin of these individuals (figure 2). The increase in GMT of antibody to A/FMjI /47 virus from I :26 in sera obtained before vaccination to I: 167
100
~A/PR/34 80 IZ
Figure 2. Percentages of persons having fourfold or greater rises in titer of HAl antibody to indicated strain of influenza A virus after one dose (200, 400, or 800 chick cellagglutinating units) of influenza A/ New Jersey(NJ)/76 virus vaccines (provided by Merrell-National Laboratories, Cincinnati, Ohio; Merck Sharp and Dohme, West Point, Pa.; or Wyeth Laboratories, Philadelphia, Pa.).
TA/NJ/76
~ 60 D:: W
a 40 20
312
1324
25-
34
3551
~52
No.TESTED 135
83
89
85
73
AGE (yrs)
3-
1324
25-
12
34
3551
~52
137
81
91
85
73
Downloaded from http://jid.oxfordjournals.org/ at Boston University on August 3, 2015
NOTE. Data are given as the percentages of persons with titers of HAl antibody of ;;;'1:20 to the indicated strain of influenza virus. A/NJ/76 = A/New Jersey/8/76; A/PR/34 = A/PR/8/34; A/FM/47 = A/FM/1/47; A/Jpn/57 = A/Japan/ 305/57; and A/Vic/75 = A/Victoria/3/75. *The numbers of sera used for a comparison of A/Victoria/ 3/75 and A/New Jersey/76 antibody responses were 146, 73, 135, 189, and 69 for those aged three to 12, 13-24, 25-34,35-51, and ;;;'52, respectively (figure 3).
A/NJ/ 76
Age-Related Antibody Responses
5689
100
Figure 3. Percentages of persons having fourfold or greater rises in titer of HAl antibody to indicated strain of influenza A virus after one dose (200, 400, or 800 chick cellagglutinating units) of influenza A/ New Jersey(NJ)/76 virus vaccines (provided by Merrell-National Laboratories, Cincinnati, Ohio; Merck Sharp and Dohme, West Point, Pa.; or Wyeth Laboratories, Philadelphia, Pa.}, A/Jap/57 = A/Japan/57 virus, and A/Vic/7 5 = A/Victoria/ 75 virus.
T
TA/NJ/76
A/NJ/76
.....
z
~ 60 0::: W
a.. 40 20
a
1324
2534
3551
No.TESTED 133
82
90
86
100
312
~52
1324
2534
3551
~52
73
135
189
69
146
73
of rises in titers of antibody to A/New Jersey virus was higher in the three- to 12-year age group, born during the H3N2 virus era (figures I and 3), than in other age groups. Heterologous Hswl antibody responses to infection or vaccination with H3N2 virus. The rate of heterologous Hsw I antibody response to infection with H3N2 viruses was examined in sera collected between January 1975 and March 1976. Of 128 pairs of acute- and convalescent-phase sera exhibiting a fourfold or greater rise in titer of antibody to either A/Port Chalmers/l/73 or A/ Victoria/ 3/75 virus, four (3%) also had a rise in titer of antibody to the Hsw I antigen (table 3). These rises were seen with or without preexisting Hsw I antibody in those older or younger than 50 years. The heterologous Hswl antibody response was II % after vaccination with whole-virus products containing 700 CCA units of influenza A H3N2 A/FM/47
A/PR/34
o
PRE
o
PRE
•
POST
•
POST
80
I-
~60
o
0:::
w
0..40
20
O~=--"""':=
AGE (yrs) 3-12 13-?4 25-34 35-51 No.TESTED 135 83 89 85
~52
73
3-12 13-24 25-34 35-51 137 81 91 85
~52
73
Downloaded from http://jid.oxfordjournals.org/ at Boston University on August 3, 2015
312
AGE (yrs )
in sera obtained after vaccination in this age group also reflects this phenomenon (table 2). The frequencies of fourfold or greater antibody responses to A/Japan/305/57 virus after vaccination with A/New Jersey /76 virus did not differ between the 13- to 24-year age group, which had its primary infection with this strain, and the 25- to 34-year age group (figure 3). Likewise, the ratios of GMTs of antibody to A/Japan / 57 virus in the sera obtained before and after vaccination are similar in these two age groups (table 2). The very high prevalence of antibody to A/Japan/57 virus before vaccination in those 13-24 years old (figure 5) may have dampened the response. The heterologous A/Victoria/3/75 antibody response after vaccination with A/New Jersey / 76 virus was low in all age groups, although the proportion of rises in levels of heterologous antibody to A/Victoria virus to the total number
Figure 4. Percentages of persons with titers of HAl antibody to indicated strain of influenza virus of ~ 1: 40 before and after vaccination with A/New Jersey/76 virus (200, 400, or 800 chick cell-agglutinating units) vaccines (provided by MerrellNational Laboratories, Cincinnati, Ohio; Merck Sharp and Dohme, West Point, Pa; or Wyeth Laboratories, Philadelphia, Pa.).
~A/VIC/75
~A/JAP/57 80
5690
Noble et al.
too
A/JAP/57
A/VIC/75
D
PRE
o
PRE
•
POST
•
POST
80 ~
~ 60
o a:: w a.. 40 20
13-24 25·34 35-51 82 90 86
~52
73
3-12 146
13-24 25-34 35-51 73 135 189
component and 300-500 CCA units of influenza B virus. Rises in titers of heterologous antibody occurred in persons with and without preexisting Hswl antibody, older or younger than 51 years (table 4). When the antibody response to vaccination with A/Victoria/3/75 virus in the 1976 influenza virus vaccine test program was examined, the heterologous Hswl antibody response observed was lower than that in the earlier H3N2 virus vaccine groups. Only two of 174 recipients of vaccine with a rise in titer of antibody to A/ Victoria virus also had a rise in the level of antibody to Hswl (table 4). No rise in titers of antibody to Hswl occurred in recipients of vaccine Table 3. Rises in titers of HAl antibody to influenza virus antigen Hswl among subjects with serologically confirmed infections with influenza A (H3N2) virus.
Age (years) 3-12 13-24 25-34 35-51 ~52
Total
No. tested 5 80 9 13 21 128
No. with fourfold or greater rise in Hsw 1 antibody titer (%)*
2
4 (3)
NOTE. All subjects had fourfold or greater rises in titer of antibody to A/Port Chalmers/l/73 or A/Victoria/3/75 viruses between January 1975 and March 1976. *The ratios of reciprocal antibody titers to A/New Jersey/ 76 virus or A/Mayo Clinic/l03/74 virus before and after vaccination for the four cases were (in order) < 10/20,
