THE JOURNAL OF INFECTIOUS DISEASES· VOL. 133. NO.4· APRIL 1976 © 1976 by the University of Chicago. All rights reserved.
Reactions to Rubella Vaccine and Persistence of Antibody in Virgin-Soil Populations after Vaccination and Wild-Virus-Induced Immunization From the Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut; the National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland,' and the Instituto Evandro Chagas, FOC, Brazilian Ministry of Health, Belem, Para, Brazil
Francis L. Black, Steven H. Lamm, Jean E. Emmons, and Francisco P. Pinheiro
persons who have been infected but whose titers have fallen below some threshold, and (2) reinfections may elicit booster responses during longterm follow-up study. However, when prescreening showed no measurable antibody in sera from any member of two very isolated Amazon Indian populations (the Xikrin and the Mekranoti) [1], we concluded that we were dealing with groups who had had no prior experience with rubella virus and whose reactions would not be modified by marginal levels of immunity. A third, similarly isolated group (the Tiriyo) had experienced a rubella epidemic in the early 1960s; most persons born before that date had antibody, but those born subsequently did not. This situation offered us the opportunity to study the pattern of naturally acquired antibody in the absence of reinfection. A major reason for this study was to determine the safety of rubella vaccine in a virgin population. Because of the current highway building program in the Amazon basin, tribes of the area will be much more frequently exposed to exogenous viruses than heretofore. It seemed advisable,
Elements of uncontrolled variability exist in the results of most rubella vaccination trials, because (1) prescreening by HAl tests does not exclude Received for publication June 2, 1975, and in revised form November 18, 1975. This work was supported by research grant no. AI00701 from the National Institute of Allergy and Infectious Diseases, by travel grants from the Pan American Health Organization, and by Superintendencia de Desenvolvimento da Amazonia. Dr. Pinheiro is the recipient of a grant from the Brazilian National Research Council. We are grateful to Dr. S. Plotkin for arranging the vaccine supply; to the Fundacao Nacional do Indio, Brazil, the Franciscan Mission at Tiriyo, Dr. Lux Vidal, and Ms. Ruth Thomson for help in the field; and to Dr. D. M. Horstmann for advice and serological laboratory facilities. This study was reviewed and approved before its initiation by the Human Investigations Committee of Yale University and by the Fundacao Nacional do Indio, Belem, Brazil. Please address requests for reprints to Dr. Francis L. Black, Department of Epidemiology and Public Health, Vale University School of Medicine, 60 College Street, New Haven, Connecticut 06510.
393
Downloaded from http://jid.oxfordjournals.org/ at Yale University on June 29, 2015
Vaccination of two virgin-soil (without historical or serological evidence of past infection) populations of Amazon Indians with RA 27/3 rubella vaccine was followed by fever of > 100 F in 10% of the vacinees and by ephemeral arthralgia in 2 %. These frequencies are not greater than those that have been reported for cosmopolitan populations of comparable ages. There was little or no secondary spread of the virus. Titers of hemagglutination-inhibiting antibody to rubella virus were prevalent in a third population of Amazon Indians, who had naturally acquired immunity and were unexposed to reinfection, and did not decline during a period of four to 12 years after infection. Antibody titers in the two virgin-soil populations immunized with RA 27/3 vaccine declined by twofold between four months and two and one-half years after vaccination but, at the end of that period, were not appreciably lower than antibody titers at four years in the naturally infected population. All age groups except children under one year of age responded to vaccination equally well.
Black et al.
394
before recommending general use of vaccine, to conduct a careful study of vaccine effects. Materials and Methods
Populations.
1 The terms "virgin" and "virgin-soil" are used to indicate a population without historical or serological evidence of past infection by the disease in question.
Results
Vaccine reaction. None of 92 serum specimens collected from the Xikrin in 1970 had rubella HAl antibody demonstrable at a dilution of 1: 8. The reactions observed after vaccination were minimal (table 1). During the second week after vaccination, nine of 86 vaccinees and one of 51 controls had temperatures of ~ 100 F. Only one vaccinee had a temperature of > 102 F; this individual was a child of 11 months who had a fever of 103.2 on day 13. The average body temperature in the vaccinees was elevated above that in the controls by approximately 0.4 F from day 10 to day 12 (figure 1). The temperature elevation during this period was observable in each major age group when examined separately as well as in the population as a whole. Arthralgia was noted in nine (26%) of 35 vaccinated adult males for one or two days during the third week after vaccination. The wrist was the joint most commonly involved. There were no similar complaints from the younger age groups or from the unvaccinated women during this period.
Downloaded from http://jid.oxfordjournals.org/ at Yale University on June 29, 2015
The populations studied have been described previously [1]. The tribes were sufficiently isolated to have remained virgin-soilwith respect to measles, mumps, influenza, and various other viral infections. Travel into the tribal areas was almost entirely confined to infrequent official business, and travel out by the Indians was confined to a few extended visits for medical treatment. The Indians kept no record of age; except for infants, ages were therefore only estimated. Participants were identified by a missionary who lived with the tribes and knew each member. Nevertheless, our informant changed on separate visits and, because the Indians changed names, misidentification was possible. Because of this possibility, detailed consideration of the few instances in which paired sera showed major changes in titer was considered unwarranted. The Tiriyo are a Carib tribe whose territory straddles the Brazil-Surinam border. At the time of the rubella epidemic, they lived in several wellseparated villages [2], but the study was done at the Brazilian mission, where approximately 200 persons had gathered by 1966. The Xikrin and Mekranoti are two Kayapo groups who live 300 miles apart in the southern part of Para State. There were about 130 Xikrin and 190 Mekranoti. Vaccine. The vaccine used was the RA 27/3 strain [3] supplied by Burroughs-Wellcome (Beckenham, England). Serum specimens were collected before vaccination, and vaccine was administered sc to males of all ages and to prepubescent girls of the Xikrin and Mekranoti tribes in May and June of 1972, respectively. Daily (afternoon) axillary temperatures were measured from day 8 to day 21 after vaccination; those who were unvaccinated served as controls. This strain of vaccine is reported to produce an immune response more like that to the wild virus [4]
than that to the strains more commonly used in the United States [5, 6]. Serum specimens. Specimens of serum were collected from the Tiriyo in 1966, 1970, and 1974 (approximately four, eight, and 12 years after the rubella epidemic). Specimens from the Xikrin were collected two years before vaccination, at the time of vaccination, and 26 months after vaccination. Specimens from the Mekranoti were collected three years before vaccination, at the time of vaccination, and four and one-half and 29 months after vaccination. On each occasion, some members of the tribe were absent, and serial specimens from the same persons were not always available. Serological tests. Tests for rubella HAl antibody were done according to the method of Liebhaber [7]. The lowest dilution tested in about half of the sera was 1: 4 and in nearly all others was 1: 8. Only one specimen that was positive at a dilution of 1: 4 was not positive at 1: 8 as well. Data from these two series of specimens are combined and, if negative, are recorded as < 1: 8.
Rubella Vaccine in Amazon Indians
Table 1.
395
Reactions of the Xikrin tribe to vaccination with RA 27/3 rubella vaccine. Vaccination status Vaccinated No. with fever No.
;;:=: 100F
No. with arthralgia
32 19 35
4 3 2
0 0 9
Group
(age in years, sex) * ~/12-6, M and F 6-14, M and F ;;:=: 15, M ;;:=: 15, F
* M = male;
Unvaccinated No.
;;:=: 100 F
No. with arthralgia
12 4
0 0
0 0
No. with fever
35 F
0
= female.
Titers of antibody after natural infection.
98.5
.....
J
w
:r Z
w
0:
~
u,
",
en w w
\
0:
98.0
~
\ACCINEE
X"--x~
----, ,,.-,
C)
W 0
x~
/
'
//
.------.
..........
Reactions to Rubella Vaccine and Persistence of Antibody in Virgin-Soil Populations after Vaccination and Wild-Virus-Induced Immunization From the Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut; the National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland,' and the Instituto Evandro Chagas, FOC, Brazilian Ministry of Health, Belem, Para, Brazil
Francis L. Black, Steven H. Lamm, Jean E. Emmons, and Francisco P. Pinheiro
persons who have been infected but whose titers have fallen below some threshold, and (2) reinfections may elicit booster responses during longterm follow-up study. However, when prescreening showed no measurable antibody in sera from any member of two very isolated Amazon Indian populations (the Xikrin and the Mekranoti) [1], we concluded that we were dealing with groups who had had no prior experience with rubella virus and whose reactions would not be modified by marginal levels of immunity. A third, similarly isolated group (the Tiriyo) had experienced a rubella epidemic in the early 1960s; most persons born before that date had antibody, but those born subsequently did not. This situation offered us the opportunity to study the pattern of naturally acquired antibody in the absence of reinfection. A major reason for this study was to determine the safety of rubella vaccine in a virgin population. Because of the current highway building program in the Amazon basin, tribes of the area will be much more frequently exposed to exogenous viruses than heretofore. It seemed advisable,
Elements of uncontrolled variability exist in the results of most rubella vaccination trials, because (1) prescreening by HAl tests does not exclude Received for publication June 2, 1975, and in revised form November 18, 1975. This work was supported by research grant no. AI00701 from the National Institute of Allergy and Infectious Diseases, by travel grants from the Pan American Health Organization, and by Superintendencia de Desenvolvimento da Amazonia. Dr. Pinheiro is the recipient of a grant from the Brazilian National Research Council. We are grateful to Dr. S. Plotkin for arranging the vaccine supply; to the Fundacao Nacional do Indio, Brazil, the Franciscan Mission at Tiriyo, Dr. Lux Vidal, and Ms. Ruth Thomson for help in the field; and to Dr. D. M. Horstmann for advice and serological laboratory facilities. This study was reviewed and approved before its initiation by the Human Investigations Committee of Yale University and by the Fundacao Nacional do Indio, Belem, Brazil. Please address requests for reprints to Dr. Francis L. Black, Department of Epidemiology and Public Health, Vale University School of Medicine, 60 College Street, New Haven, Connecticut 06510.
393
Downloaded from http://jid.oxfordjournals.org/ at Yale University on June 29, 2015
Vaccination of two virgin-soil (without historical or serological evidence of past infection) populations of Amazon Indians with RA 27/3 rubella vaccine was followed by fever of > 100 F in 10% of the vacinees and by ephemeral arthralgia in 2 %. These frequencies are not greater than those that have been reported for cosmopolitan populations of comparable ages. There was little or no secondary spread of the virus. Titers of hemagglutination-inhibiting antibody to rubella virus were prevalent in a third population of Amazon Indians, who had naturally acquired immunity and were unexposed to reinfection, and did not decline during a period of four to 12 years after infection. Antibody titers in the two virgin-soil populations immunized with RA 27/3 vaccine declined by twofold between four months and two and one-half years after vaccination but, at the end of that period, were not appreciably lower than antibody titers at four years in the naturally infected population. All age groups except children under one year of age responded to vaccination equally well.
Black et al.
394
before recommending general use of vaccine, to conduct a careful study of vaccine effects. Materials and Methods
Populations.
1 The terms "virgin" and "virgin-soil" are used to indicate a population without historical or serological evidence of past infection by the disease in question.
Results
Vaccine reaction. None of 92 serum specimens collected from the Xikrin in 1970 had rubella HAl antibody demonstrable at a dilution of 1: 8. The reactions observed after vaccination were minimal (table 1). During the second week after vaccination, nine of 86 vaccinees and one of 51 controls had temperatures of ~ 100 F. Only one vaccinee had a temperature of > 102 F; this individual was a child of 11 months who had a fever of 103.2 on day 13. The average body temperature in the vaccinees was elevated above that in the controls by approximately 0.4 F from day 10 to day 12 (figure 1). The temperature elevation during this period was observable in each major age group when examined separately as well as in the population as a whole. Arthralgia was noted in nine (26%) of 35 vaccinated adult males for one or two days during the third week after vaccination. The wrist was the joint most commonly involved. There were no similar complaints from the younger age groups or from the unvaccinated women during this period.
Downloaded from http://jid.oxfordjournals.org/ at Yale University on June 29, 2015
The populations studied have been described previously [1]. The tribes were sufficiently isolated to have remained virgin-soilwith respect to measles, mumps, influenza, and various other viral infections. Travel into the tribal areas was almost entirely confined to infrequent official business, and travel out by the Indians was confined to a few extended visits for medical treatment. The Indians kept no record of age; except for infants, ages were therefore only estimated. Participants were identified by a missionary who lived with the tribes and knew each member. Nevertheless, our informant changed on separate visits and, because the Indians changed names, misidentification was possible. Because of this possibility, detailed consideration of the few instances in which paired sera showed major changes in titer was considered unwarranted. The Tiriyo are a Carib tribe whose territory straddles the Brazil-Surinam border. At the time of the rubella epidemic, they lived in several wellseparated villages [2], but the study was done at the Brazilian mission, where approximately 200 persons had gathered by 1966. The Xikrin and Mekranoti are two Kayapo groups who live 300 miles apart in the southern part of Para State. There were about 130 Xikrin and 190 Mekranoti. Vaccine. The vaccine used was the RA 27/3 strain [3] supplied by Burroughs-Wellcome (Beckenham, England). Serum specimens were collected before vaccination, and vaccine was administered sc to males of all ages and to prepubescent girls of the Xikrin and Mekranoti tribes in May and June of 1972, respectively. Daily (afternoon) axillary temperatures were measured from day 8 to day 21 after vaccination; those who were unvaccinated served as controls. This strain of vaccine is reported to produce an immune response more like that to the wild virus [4]
than that to the strains more commonly used in the United States [5, 6]. Serum specimens. Specimens of serum were collected from the Tiriyo in 1966, 1970, and 1974 (approximately four, eight, and 12 years after the rubella epidemic). Specimens from the Xikrin were collected two years before vaccination, at the time of vaccination, and 26 months after vaccination. Specimens from the Mekranoti were collected three years before vaccination, at the time of vaccination, and four and one-half and 29 months after vaccination. On each occasion, some members of the tribe were absent, and serial specimens from the same persons were not always available. Serological tests. Tests for rubella HAl antibody were done according to the method of Liebhaber [7]. The lowest dilution tested in about half of the sera was 1: 4 and in nearly all others was 1: 8. Only one specimen that was positive at a dilution of 1: 4 was not positive at 1: 8 as well. Data from these two series of specimens are combined and, if negative, are recorded as < 1: 8.
Rubella Vaccine in Amazon Indians
Table 1.
395
Reactions of the Xikrin tribe to vaccination with RA 27/3 rubella vaccine. Vaccination status Vaccinated No. with fever No.
;;:=: 100F
No. with arthralgia
32 19 35
4 3 2
0 0 9
Group
(age in years, sex) * ~/12-6, M and F 6-14, M and F ;;:=: 15, M ;;:=: 15, F
* M = male;
Unvaccinated No.
;;:=: 100 F
No. with arthralgia
12 4
0 0
0 0
No. with fever
35 F
0
= female.
Titers of antibody after natural infection.
98.5
.....
J
w
:r Z
w
0:
~
u,
",
en w w
\
0:
98.0
~
\ACCINEE
X"--x~
----, ,,.-,
C)
W 0
x~
/
'
//
.------.
..........
