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IMPAIRMENT OF THE IMMUNE RESPONSE TO VACCINATION AFTER ACUTE MALARIA
1328
IMPAIRMENT OF THE IMMUNE RESPONSE TO VACCINATION AFTER ACUTE MALARIA B. M. GREENWOOD
W. A. WILLIAMSON*
Endemic Diseases Research Unit and Department of Ahmadu Bello
Medicine,
University, Zaria, Nigeria
Children with acute malaria were vaccinated with Salmonella typhi and meningococcal vaccines at varying times after the onset of their illness. The immune response to both vaccines was depressed when they were given on the day of presentation at hospital. Immune responsiveness to S. typhi vaccine was rapidly regained after treatment, but a month after the attack the immune response to meningococcal vaccine was still impaired.
Summary
Introduction
parasitic infections, including malaria, are accompanied by immunosuppression. 1,2 The possible consequences of this phenomenon for people living in areas of high malaria endemicity, where recurrent attacks of malaria occur throughout childhood, are un-, known. However, it has been suggested that repeated episodes of malaria-induced immunosuppression may contribute to the high incidence of bacterial infections observed among children in the tropics, may interfere with vaccination programmes, and may have other longterm effects such as predisposing to the development of Burkitt’s lymphoma. Investigations of malaria-induced immunosuppression in animals have shown that humoral immunity is affected more than cellular immunity3 and that a defect in the processing of antigen by macrophages is probably involved in its pathogenesis.4-6 Disappearance of parasites from the circulation usually results in a rapid return of immune competence, but immunodepression 8 may persist in chronically infected animals. 7 Little is known about the immunosuppressive effects of malaria in man. In 1962 it was reported that children receiving regular malaria prophylaxis had a better antibody response to tetanus vaccine than unprotected children living in the same environment.9 10 years later it was shown that the antibody response to tetanus and Salmonella typhi vaccines was much reduced in children with acute Plasmodium falciparum malaria although MANY
of Harof at least 1%. None was wasted (<80% of Harvard vard standard weight for height) or stunted (<90% standard height for age) or had any underlying disease. Their ages ranged from 6 months to 6 years (mean 3.1 years). 40 healthy’afebrile siblings matched for age, sex, and ethnic group acted as controls. None had detectable malaria parasitsemia.
parasitaemia
Outline
of Study
Children with acute malaria were randomly allocated to one of three groups. Children in group(28) were immunised at the time of their presentation at hospital with S. typhi vaccine (Burroughs Wellcome), 0.1ml intradermally, and group-C meningococcal vaccine (Institut Merieux), 0-5 ml intramuscularly. Group II (25) received the same immunisations 7 days after presentation with acute malaria, and group III (26) were vaccinated 28 days after presentation. All children were treated immediately with chloroquine and any other treatment thought to be necessary. Weekly pyrimethamine was given to patients and controls to prevent any further attacks of malaria during the study period. Examination of blood-films confirmed successful prophylaxis. Capillary samples were collected immediately before and two weeks after vaccination.
Laboratory Methods Hasmatological counter.
5
indices
were
determined with
a
Coulter ZF
µl. of blood was added directly to a measured volume
counting fluid at the time of blood collection. Parasite density was calculated from the red-blood-cell count and from the of
number of infected red blood cells observed in a Leishmanstained thin blood-smear. Antibodies to the 0 antigen of S. typhi were measured with a microtitre Widal test. Antibodies to the meningococcal vaccine were measured with a hamiagglutination technique using human group-0 red blood cells coated with purified group-C meningococcal polysaccharide. Responders to immunisation have been defiried as subjects who showed a rise in antibody titre of at least 2 doubling dilutions following vaccination.
Results
The mean rises in antibody titre of children given S. typhi and meningococcal vaccines at varying times after the onset of an attack of acute malaria are shown in figs. 1 and 2. The antibody response to both vaccines was significantly reduced (P<0.01) when the vaccines were given on the first day of illness. 7 days later the antibody response to S. typhi vaccine had returned to normal.
cellular immune responses were retained.10 It was not established for how long this immune defect persisted. A transient defect is likely to be of little significance but a more prolonged period of immunosuppression could be of considerable clinical importance. We have therefore studied the immune response of children with acute P. falciparum malaria to vaccination with S. typhi and meningococcal vaccines given at varying times after the onset of their illness. Patients and Methods Patients and Controls 79 children who
presented
at
Ahmadu Bello University
tal, Malumfashi, Nigeria with were
acute
P.
studied. All had clinical features of acute
*Dr Williamson died
on
Jan. 20, 1978.
Hospi-
malaria malaria and a
falciparum
1-Mean increase in antibody titre (±1s.E.) following vaccination with S. typhi vaccine at varying times after an attack of acute P. falciparum malaria and in healthy controls.
Fig.
1329
2-Mean increase in antibody titre (±1 1 s.F.) following vaccination with meningococcal vaccine at varying times after an attack of acute P. falciparum malaria and in healthy controls.
Fig.
However, 7 days and 28 days after an attack of
acute
malaria the antibody response to meningococcal vaccine was still significantly less than in the healthy controls (p <005 in each case). The relationship between the antibody response to vaccination on the first day of illness and the height of malaria parasitsemia was determined. For both S. typhi vaccine and meningococcal vaccine a significant negative correlation was found between the rise in antibody titre (logic) and the absolute parasite count (loglo) (r - 0.65, p 0.001; and r = -0.59, p 0.001 respecti=
=
=
vely). When the vaccines were given on the first day of illthe proportion of responders to both vaccines was
ness
RESPONDERS TO VACCINATION AMONG HEALTHY CHILDREN AND
AMONG CHILDREN WITH ACUTE MALARIA
* Days shown are counted from the day of presentation at hospital.
less than that of controls (see table). When the vaccines were given 7 days after the onset of illness the proportion of responders to meningococcal, but not to S. typhi vaccine, was still significantly reduced. Discussion These results confirm our previous findings10 that an attack of acute P. falciparum malaria is immunosuppressive. A significant correlation was found between the height of parasitæmia and the degree of immunosuppression, children with the highest parasitæmias making no antibody response to vaccination. After treatment immune responsiveness to S. typhi vaccine rapidly returned. However, recovery of immune responsiveness to meningococcal vaccine was delayed. 7 days after an
attack of acute malaria both the mean rise in antibody titre following meningococcal vaccination and the number of responders were still significantly less than in the controls. 3 weeks later the mean rise in antibody titre was still significantly depressed, although the number of responders did not now differ significantly from the controls. We are uncertain which of these criteria is the most appropriate indicator of the effect of malaria on the response to a vaccine, for in practical terms the important factor is whether malaria can interfere with the ability of a vaccine to protect against the disease for which it is given. This has yet to be shown. The more pronounced depressive effect of malaria on meningococcal vaccine than on S. typhi vaccine may be related to the fact that the group-C meningococcal vaccine evoked a predominantly primary immune response in the patients studied and to the fact that this vaccine is relatively poorly immunogenic in young children." Our results suggest that an attack of acute malaria can, even when treated promptly, have a prolonged depressive effect on the humoral immune system. An alternative explanation for our findings does, however, need to be considered. Even in an entirely healthy population a small proportion of individuals show little or no
meningococcal polysaccharide vaccines, perhaps because of a genetically determined immune defect. It is possible that this group of non-responders is overrepresented among children developing malaria severe enough to require hospital treatment and that the children in this study would never have had a normal immune response to meningococcal vaccine, even when quite healthy. This possibility requires further investigation, but we think that it is a less likely explanation of our findings than that the immunodepression observed response to
in these children was related to their recent attack of malaria. Acute attacks of clinical malaria are relatively u’ricommon, even in areas of high malaria endemicity. However, children living in these areas often have episodes of moderately heavy parasitaemia which are accompanied by little in the way of clinical symptoms. Studies are now in progress to determine whether asymptomatic parasitaemia has an immunosuppressive effect and whether this is severe enough to interfere with the practical success of a vaccination programme. We thank Prof. H. M. Gilles and Dr D. B. Musa for their help and encouragement. This study was supported by the Medical Research Council.
Requests for reprints should be addressed to B. M. G., Department of Medicine, Ahmadu Bello University Hospital, Zaria, Nigeria. REFERENCES B. M. in Parasites in the Immunised Host: mechanisms of survival (edited by R. Porter and J. Knight); p. 137. Amsterdam, 1974. 2. Terry, R. J. in Immunity in Parasitic Diseases: antigens and mechanisms of immune response (edited by P. Pery and A. Capron) (in the press). 3. Greenwood, B. M., Playfair, J. H. L., Torrigiani, G. Clin. exp. Immun 1.
Greenwood,
1971, 8, 467. Cook, J. A., 39, 484.
4 Loose, L. D.,
di Luzio, N. R. Proc. helminth. Soc. Wash. 1972,
5. Warren, H. S., Weidanz, W. P. Eur. J. Immun. 1976, 6, 816. 6. Brown, I. N., Watson, S. R., Slijivić, V. S. Infect. Immunity, 1977, 16, 456. 7. McBride, J. S., Micklem, H. S., Ure, J. M. Immunology, 1977, 32, 635. 8 Wedderburn, N., Dracott, B. N. Clin. exp. Immun. 1977, 28, 130. 9. McGregor, I. A., Barr, M. Trans. R. Soc. trop. Med. Hyg. 1962, 56, 364. 10. Greenwood, B. M., Bradley-Moore, A M., Palit, A., Bryceson, A. D. M. 11.
Lancet, 1972, i, 169. Goldschneider, I., Lepow, 509.
M.
L., Gotschlich, E. C. J. infect. Dis. 1972, 125,
IMPAIRMENT OF THE IMMUNE RESPONSE TO VACCINATION AFTER ACUTE MALARIA B. M. GREENWOOD
W. A. WILLIAMSON*
Endemic Diseases Research Unit and Department of Ahmadu Bello
Medicine,
University, Zaria, Nigeria
Children with acute malaria were vaccinated with Salmonella typhi and meningococcal vaccines at varying times after the onset of their illness. The immune response to both vaccines was depressed when they were given on the day of presentation at hospital. Immune responsiveness to S. typhi vaccine was rapidly regained after treatment, but a month after the attack the immune response to meningococcal vaccine was still impaired.
Summary
Introduction
parasitic infections, including malaria, are accompanied by immunosuppression. 1,2 The possible consequences of this phenomenon for people living in areas of high malaria endemicity, where recurrent attacks of malaria occur throughout childhood, are un-, known. However, it has been suggested that repeated episodes of malaria-induced immunosuppression may contribute to the high incidence of bacterial infections observed among children in the tropics, may interfere with vaccination programmes, and may have other longterm effects such as predisposing to the development of Burkitt’s lymphoma. Investigations of malaria-induced immunosuppression in animals have shown that humoral immunity is affected more than cellular immunity3 and that a defect in the processing of antigen by macrophages is probably involved in its pathogenesis.4-6 Disappearance of parasites from the circulation usually results in a rapid return of immune competence, but immunodepression 8 may persist in chronically infected animals. 7 Little is known about the immunosuppressive effects of malaria in man. In 1962 it was reported that children receiving regular malaria prophylaxis had a better antibody response to tetanus vaccine than unprotected children living in the same environment.9 10 years later it was shown that the antibody response to tetanus and Salmonella typhi vaccines was much reduced in children with acute Plasmodium falciparum malaria although MANY
of Harof at least 1%. None was wasted (<80% of Harvard vard standard weight for height) or stunted (<90% standard height for age) or had any underlying disease. Their ages ranged from 6 months to 6 years (mean 3.1 years). 40 healthy’afebrile siblings matched for age, sex, and ethnic group acted as controls. None had detectable malaria parasitsemia.
parasitaemia
Outline
of Study
Children with acute malaria were randomly allocated to one of three groups. Children in group(28) were immunised at the time of their presentation at hospital with S. typhi vaccine (Burroughs Wellcome), 0.1ml intradermally, and group-C meningococcal vaccine (Institut Merieux), 0-5 ml intramuscularly. Group II (25) received the same immunisations 7 days after presentation with acute malaria, and group III (26) were vaccinated 28 days after presentation. All children were treated immediately with chloroquine and any other treatment thought to be necessary. Weekly pyrimethamine was given to patients and controls to prevent any further attacks of malaria during the study period. Examination of blood-films confirmed successful prophylaxis. Capillary samples were collected immediately before and two weeks after vaccination.
Laboratory Methods Hasmatological counter.
5
indices
were
determined with
a
Coulter ZF
µl. of blood was added directly to a measured volume
counting fluid at the time of blood collection. Parasite density was calculated from the red-blood-cell count and from the of
number of infected red blood cells observed in a Leishmanstained thin blood-smear. Antibodies to the 0 antigen of S. typhi were measured with a microtitre Widal test. Antibodies to the meningococcal vaccine were measured with a hamiagglutination technique using human group-0 red blood cells coated with purified group-C meningococcal polysaccharide. Responders to immunisation have been defiried as subjects who showed a rise in antibody titre of at least 2 doubling dilutions following vaccination.
Results
The mean rises in antibody titre of children given S. typhi and meningococcal vaccines at varying times after the onset of an attack of acute malaria are shown in figs. 1 and 2. The antibody response to both vaccines was significantly reduced (P<0.01) when the vaccines were given on the first day of illness. 7 days later the antibody response to S. typhi vaccine had returned to normal.
cellular immune responses were retained.10 It was not established for how long this immune defect persisted. A transient defect is likely to be of little significance but a more prolonged period of immunosuppression could be of considerable clinical importance. We have therefore studied the immune response of children with acute P. falciparum malaria to vaccination with S. typhi and meningococcal vaccines given at varying times after the onset of their illness. Patients and Methods Patients and Controls 79 children who
presented
at
Ahmadu Bello University
tal, Malumfashi, Nigeria with were
acute
P.
studied. All had clinical features of acute
*Dr Williamson died
on
Jan. 20, 1978.
Hospi-
malaria malaria and a
falciparum
1-Mean increase in antibody titre (±1s.E.) following vaccination with S. typhi vaccine at varying times after an attack of acute P. falciparum malaria and in healthy controls.
Fig.
1329
2-Mean increase in antibody titre (±1 1 s.F.) following vaccination with meningococcal vaccine at varying times after an attack of acute P. falciparum malaria and in healthy controls.
Fig.
However, 7 days and 28 days after an attack of
acute
malaria the antibody response to meningococcal vaccine was still significantly less than in the healthy controls (p <005 in each case). The relationship between the antibody response to vaccination on the first day of illness and the height of malaria parasitsemia was determined. For both S. typhi vaccine and meningococcal vaccine a significant negative correlation was found between the rise in antibody titre (logic) and the absolute parasite count (loglo) (r - 0.65, p 0.001; and r = -0.59, p 0.001 respecti=
=
=
vely). When the vaccines were given on the first day of illthe proportion of responders to both vaccines was
ness
RESPONDERS TO VACCINATION AMONG HEALTHY CHILDREN AND
AMONG CHILDREN WITH ACUTE MALARIA
* Days shown are counted from the day of presentation at hospital.
less than that of controls (see table). When the vaccines were given 7 days after the onset of illness the proportion of responders to meningococcal, but not to S. typhi vaccine, was still significantly reduced. Discussion These results confirm our previous findings10 that an attack of acute P. falciparum malaria is immunosuppressive. A significant correlation was found between the height of parasitæmia and the degree of immunosuppression, children with the highest parasitæmias making no antibody response to vaccination. After treatment immune responsiveness to S. typhi vaccine rapidly returned. However, recovery of immune responsiveness to meningococcal vaccine was delayed. 7 days after an
attack of acute malaria both the mean rise in antibody titre following meningococcal vaccination and the number of responders were still significantly less than in the controls. 3 weeks later the mean rise in antibody titre was still significantly depressed, although the number of responders did not now differ significantly from the controls. We are uncertain which of these criteria is the most appropriate indicator of the effect of malaria on the response to a vaccine, for in practical terms the important factor is whether malaria can interfere with the ability of a vaccine to protect against the disease for which it is given. This has yet to be shown. The more pronounced depressive effect of malaria on meningococcal vaccine than on S. typhi vaccine may be related to the fact that the group-C meningococcal vaccine evoked a predominantly primary immune response in the patients studied and to the fact that this vaccine is relatively poorly immunogenic in young children." Our results suggest that an attack of acute malaria can, even when treated promptly, have a prolonged depressive effect on the humoral immune system. An alternative explanation for our findings does, however, need to be considered. Even in an entirely healthy population a small proportion of individuals show little or no
meningococcal polysaccharide vaccines, perhaps because of a genetically determined immune defect. It is possible that this group of non-responders is overrepresented among children developing malaria severe enough to require hospital treatment and that the children in this study would never have had a normal immune response to meningococcal vaccine, even when quite healthy. This possibility requires further investigation, but we think that it is a less likely explanation of our findings than that the immunodepression observed response to
in these children was related to their recent attack of malaria. Acute attacks of clinical malaria are relatively u’ricommon, even in areas of high malaria endemicity. However, children living in these areas often have episodes of moderately heavy parasitaemia which are accompanied by little in the way of clinical symptoms. Studies are now in progress to determine whether asymptomatic parasitaemia has an immunosuppressive effect and whether this is severe enough to interfere with the practical success of a vaccination programme. We thank Prof. H. M. Gilles and Dr D. B. Musa for their help and encouragement. This study was supported by the Medical Research Council.
Requests for reprints should be addressed to B. M. G., Department of Medicine, Ahmadu Bello University Hospital, Zaria, Nigeria. REFERENCES B. M. in Parasites in the Immunised Host: mechanisms of survival (edited by R. Porter and J. Knight); p. 137. Amsterdam, 1974. 2. Terry, R. J. in Immunity in Parasitic Diseases: antigens and mechanisms of immune response (edited by P. Pery and A. Capron) (in the press). 3. Greenwood, B. M., Playfair, J. H. L., Torrigiani, G. Clin. exp. Immun 1.
Greenwood,
1971, 8, 467. Cook, J. A., 39, 484.
4 Loose, L. D.,
di Luzio, N. R. Proc. helminth. Soc. Wash. 1972,
5. Warren, H. S., Weidanz, W. P. Eur. J. Immun. 1976, 6, 816. 6. Brown, I. N., Watson, S. R., Slijivić, V. S. Infect. Immunity, 1977, 16, 456. 7. McBride, J. S., Micklem, H. S., Ure, J. M. Immunology, 1977, 32, 635. 8 Wedderburn, N., Dracott, B. N. Clin. exp. Immun. 1977, 28, 130. 9. McGregor, I. A., Barr, M. Trans. R. Soc. trop. Med. Hyg. 1962, 56, 364. 10. Greenwood, B. M., Bradley-Moore, A M., Palit, A., Bryceson, A. D. M. 11.
Lancet, 1972, i, 169. Goldschneider, I., Lepow, 509.
M.
L., Gotschlich, E. C. J. infect. Dis. 1972, 125,