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Rotavirus infections and their prevention by vaccination
Antiviral Research, Suppl. 1 (1985) 293-300 Proc. 1st Int. TNO Conf. Antiviral Res. 1985 Rotterdam A. Billiau, E. De Clercq and H. Schellekens (eds.) © 1985 Elsevier Science Publishers B.V. (Biomedical Division)
KOTAVIKUS INFECTIONS ANU THEIK PKEVENTION
~y
VACCINATION
TIMO VESIKAKI Uepartment of Clinical Sciences, University of Tampere, 33520 Tampere, Finland KOTAVIKUS INFECTIUNS Kotavirus infections in young children are characterized by acute gastroenteritis with explosive onset, watery diarrhoea, vomiting, fever, and rapid development of dehydration and acidosis (1). Kotavirus diarrhoea often requires hospitalization, and in developed countries rotaviruses are responsible for 50% or more of the hospitalized cases of acute diarrhoea in children (2). Mortality is low in developed countries, but worldwide rotavirus gastroenteritis may be responsible for 500.000 or more deaths annually (3). All rotavirus infections are not associated with gastroenteritis, however, but many are asymptomatic and some may be associated with clinical symptoms other than diarrhoea (4). In Finland, about 50% of the children experienced a rotavirus infection in the first year of life during one epidemic season, and 43% of these infections were associated with diarrhoea (Tables I and II). Severe rotavirus diarrhoea seldom occurs twice in the same child: therefore it is likely that one rotavirus infection induces cross-protection against diarrhoea in subsequent attacks of rotavirus infection. Even a neonatally acqui red asymptomatic rotavi rus infection by a "nursery strain" gives protection against rotavirus diarrhoea, but not infection, for the first 3 years of life (5). RATIONALE FUK KUTAVIKUS VACCINATIUN The goal of rotavirus vaccination would be prevention of severe diarrhoea when children are most susceptible to dehydration, i.e up to the age of 3 years. Prevention of rotavirus infections is not important and may not be possible to achieve with any vaccine. Un the contrary, attacks of natural rotavirus infection in a vaccinated subject may contribute to build-up of immunity while not causing clinical illness (Table I). In Western Europe and USA rotavirus infections mostly follow a clear seasonal pattern with epidemic peak in cold season. The field trials of rotavirus vaccine in Finland have taken advantage of this epidemiologic pattern (6). Infants aged 6 to 12 months were vaccinated before the epidemic period with the purpose of preventing rotavirus diarrhoea for the first two epidemic seasons after that age (7,H). This design could also serve as a model for rotavirus vaccination in developed countries in general. 293
There is a great need for a rotavirus vaccine in the developing countries, but there are also potential problems. Kotavirus diarrhoeas may occur before the age of half a year necessitating early vaccination. Maternal serum antibodies and breast-feeding might then inferfere with the take of rotavirus vaccine. It would also be preferrable to combine oral rotavirus and poliovirus vacci nes, but these vacci ne vi ruses mi ght i nferfere with each other. Ttlese problems are currently being investigated. Altogether prevention of diarrhoeal mortality and morbidity is more complex in developing countries. Many of the 500.000 or so annual deaths from rotavirus diarrhoea are due to dehydration and might be preventable by a rotavirus vaccine. Other deaths result from diarrhoea-mal nutrition-diarrhoea vicious circle, in which rotavirus infections may play some role. The impact of rotavirus vaccine on this morbidity and mortality will be more difficult to assess. KUTAVIKUS VACCINES Several approaches have been proposed for the development of rotavirus vaccines for humans (9). However, so far only attenuated heterologous rotavirus strains have actually been tested as vaccines for children. The KIT 4237 bovine rotavirus vaccine strain was derived from the Nebraska Calf Diarrhea Virus (NCUV) by passaging in primary foetal bovine kidney cells, and the vaccine is produced at the 154th passage level in primary monkey kidney cells suitable for human vaccine production (10). Most of this communication deals with clinical trials of this vaccine. More recently a rhesus monkey rotavi rus vaccine strain KKV-1 (I'IMU-180U6) was introduced as a candidate rotavirus vaccine for humans. This vaccine, developed by A.Z. Kapikian of NIH, is now being evaluated in clinical trials in children. PKUTECTIUN AuAINST KUTAVIKUS DIAKKHUEA
~y
THE KIT 4237 VACCINE
The clinical efficacy of the KIT 4237 vaccine was tested in two double-blind placebo-controlled field trials in Tampere, Finland (7,8). The first trial involved 190 infants aged 8 to 11 months vaccinated in January 1983. In the first epidemic season of rotavirus there were 18 episodes of rotavirus diarrhoea in the 92 placebo recipients vs. only 2 episodes in the 86 vaccine recipients who were followed for the entire season (p < U.UU1, vaccine protection rate 88%). The two cases of rotavirus diarrhoea in the vaccinees occurred in children who failed to develop an ELISA antibody response after
294
post-epidemic sera. There were 5 cases of clinically significant diarrhoea (requiring rehydration therapy) in the KIT 4237 vaccine group vs. 26 in the placebo group (p < 0.001), a protection rate of 81%. One of the 5 cases in the vaccine group had seroconverted after vaccination, the remaining four had not. In addition to cases with frank diarrhoea there were again 8 episodes with mild gastrointestinal symptoms and rotavirus in the stools. Of these 7 were in the vaccine group and only one in the placebo group. The relation of clinical illness and sero-conversion for rotavirus (i.e. primary rotavirus infection) during the epidemic season is presented in Table II. TAHLE II CLINICAL ILLNESS IN KELATION TO KOTAVIKUS INFECTION Occurrence of clinically significant diarrhoea and other gastrointestinal symptoms in rotavirus vaccinees and controls who were seronegative before the rotavirus epidemic season and seroconverted during the season
Group
KIT 4237 Placebo
Seroconversion
Symptomatic
Uiarrhoea
37/5Y (63%) 60/134(45%)
11/37 (30%) 27/60 (45%)
4/37 (11%) 26/60 (43%)
Thus 43% of the detected primary rotavirus infection episodes resulted in clinical diarrhoea in the placebo group. The KIT 4237 vaccine changed this natural history significantly: diarrhoea was present in only 11% of the rotavirus infections in the vaccinees. Even in those cases the diarrhoea was milder with a mean duration of 2.8 days as compared to 4.4 days in the placebo group. The duration of KIT 4237 vaccine-induced protection appears to last longer than over one epidemic season. Table III presents the summary of clinical follow-up during the two epidemic seasons after vaccination for the er.tire group, regardless of serological response.
295
vaccination. In addition to the two cases with clinically overt diarrhoea there were in the vaccine group seven cases of mild gastrointestinal upset associated with rotavirus; no such cases were detected in the placebo group. It appeared that the vaccination had modified the clinical symptoms of rotavirus infection in these cases. There was no protection against rotavirus infection as determined by seroconversion (7). The second field trial involved a larger number of children vaccinated well before the rotavirus epidemic season (8). A total of 347 children received two oral doses of the KIT 4237 vaccine or placebo at one month~s interval in September-Uctober 1983, and post-vaccination sera were collected from 331 in Uecember 1983. After the epidemic, a third serum specimen was collected from 291 children, which indicated good compliance in follow-up. The serological follow-up of the vaccinees is summarized in Table I TAtlLE I SERULUGICAL FULLUW-UP UF RUTAVIKUS VACCINEES Kotavirus ELISA IgG antibodies in 291 children before and after rotavirus vaccination and after an epidemic of rotavirus Vaccine Group KIT 4237 (N=146) Placebo (N=145)
No.(%) Kotavirus seropositive Prevaccination Postvaccination 20 (14%) 11 (8%)
87 (60%) 10 (7%)
Post-epidemic 124 (85%) 70 (48%)
Primarily the majority of the infants were seronegative by IgG ELISA for rotavirus, and 77 of the 146 (53%) seronegative KIT 4237 vaccinees showed seroconversion as compared to only 3 of the placebo recipients (each of the latter also experienced a rotavirus diarrhoea before the collection of the post-vaccination sera). During the epidemic season 6U of the 134 (44%) seronegative children showed seroconversion, indicating either symptomatic (Table II) or asymptomatic rotavirus infection. In the end of the epidemic season a total of 48% of the children were seropositive for rotavirus, as compared to 85% in the KIT 4237 vaccine group. In the vaccine group there were in fact more (63%) seroconversions during the epidemic season (Table II). A possible explanation is that some children may have had a delayed antibody response after vaccination, detectable only after the collection of
296
TAl:ILE II I UUKATIUN UF KOTAVIKUS VACCINE-INUUCEU PKOTECTION Kotavirus diarrhoea in recipients of RIT 4237 rotavirus vaccine and placebo during two epidemic seasons of rotavirus
Group
1st season Jan-May 1984
KIT 4237 (N=168) Placebo (N=160)
2nd season Jan-Apri 1 1985
5
1
26
7
Judged by the above data the vaccine protection rate appears to remain the same for the second year (85%) as for the first season (81%). This suggests that the primary goal of rotavirus vaccination, clinical protection against rotavirus diarrhoea up to the age of 3 years, can be achieved with the KIT 4237 vaccine. The vaccine-induced protection may also cover several rotavirus serotypes. 18 of the rotavirus isolates from cases with clinically significant diarrhoea were serotyped by Ur. TH Flewett, l:Iirmingham, and the results are presented in Table IV. TAl:ILE IV PROTECTION AGAINST KOTAVIKUS SEKOTYPES Cases of rotavirus diarrhoea associated with three different serotypes of human rotavirus in the recipients of the KIT 4237 vaccine and placebo
Human rotavirus serotypes 2 3 Total
Group
1
KIT 4237 Placebo
3
o
o
3
11
2
2
15
The apparent heterotypic (and heterosubgroup) protection induced by the RIT 4237 vaccine raises questions on the protective mechanisms after rotavirus vaccination. These questions remain largely unanswered at the moment. Clearly,
297
serum antibodies (ELISA or neutralizing antibodies) may not be the only protective factor or may not even playa significant role in protection. ENHANCEMENT UF VACCINE TAKE While the significance of serum rotavirus antibodies in protection remains questionable the serological response to vaccination can nevertheless be used as an indicator of vaccine "take". A series of experiments have been carried out to study the effect of feeding on the take rate of KIT 4237 vaccine at different dose levels. It was first discorered that the vaccine virus was labile at pH 3 and below; consequently it was easily destroyed after oral vaccination in the acid conditions of the stomach, but apparently protected by milk feeding before vaccination (II). The effect of milk formula feeding on the serological response to rotavirus vaccine is illustrated in Table V. TA~LE V DOSE KESPUNSE TU KUTAVIRUS VACCINE
Serum neutralizing antibody response in 4-6 month-old infants who received a single oral KIT 4237 vaccination immediately after milk formula feeding or after 2 hours'fasting (12)
KIT 4237 Vaccine titer
No. (%l with response Formula-fed Unfed
10. 8 • 3
14/14 (lUO%)
5/8 (63%)
10 7• 2
10/14 (71%)
4/9 (44%)
106• 3
2/12 (15%)
2/7 (29%)
The conclusion from the above study was that the RIT 4237 vaccine should be administered together with an acid neutralizing substance such as milk formula. Further, the vaccine dose should be of the order of 108 tissue culture infective doses, as was used in the clinical trials presented previously. The possible (inhibitory) effect of breast milk on rotavirus vaccination remains to be studied. This question is of great importance, since breast
298
feeding is highly recommendable in the apparent target group of rotavirus vaccination, infants aged 0 to 6 months. Uur preliminary experience suggests that breast feeding may not be inhibitory for rotavirus vaccine in children over 6 months of age, but may interfene with the vaccine take in newborns. CONCLUS IONS The ~IT 4237 attenuated bovine rotavirus vaccine appears a serious candidate for rotavirus vaccination in humans. The vaccine does not cause any appreciable symptoms in children (7,13), but oral vaccination leads to a subclinical gastrointestinal infection characterized by a low degree of virus excretion (13) and still a high serological response rate of 75-100%. The vaccine induces protective immunity against rotavirus diarrhoea for at least two years, and the protection may cover more than one serotype of rotaviruses. The RIT 4237 vaccine appears sufficiently were established for a general rotavirus vaccination in developed countries. A vaccination of infants of the age of 6 months would prevent about 75% of all cases of winter diarrhoea (7,8), and therefore lead to significant reduction in hospitalization and treatment costs. A cost-benefit analysis for rotavirus vaccine remains to be done pending formal price quotation. It seems that the dose level will have to be as high (108 ) as can easily be produced in the present cell substrate. In any case the vaccine should be affordable for developed countries. It is not known if the ~IT 4237 vaccine will be efficacious in the conditions of developing countries, and further studies one required before rotavirus vaccination will be available for the third world.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8.
Maki M (1~81) Acta Paediatr Scand 70: 107-113 Steinhoff M~ (1980) J Pediatr 96: 611-622 ~utler Te (1984) J Uiar Uis ~es 2: 137-141 Champsaur H, Henry-Amar M, (joldszmidt U et al (1984) J Infect Dis 149: 675-682 ~ishop RF, ~arnes (jL, Cipriano E, Lund E (1983) N Engl J Med 909: 72-76 Vesikari T, Maki 1"1, Isolauri E (1983) Uevelop ~iol Standard 53: 229-236 Vesikari T, Isolauri E, U-Hondt E, Uelem A, Andre FE, Lissis 6 (1984) Lancet i: 977-981 Vesikari T, Isolauri E, Uelem A et al (1985) J Pediatrics, in press
299
9. 10. 11. 12.
Kapikian AZ. Wyatt IHi. Greenberg HB et a1 (1980) Hev Infect Uis 2: 459-469 De1em A. Lobmann M. Zygraich N (1984) J Bio1 Standard 4: 443-445 Vesikari T. Iso1auri E. U-Hondt E. Ue1em A. Andre FE (1984) Lancet ii: 7UU Vesikari T. Huuska T. Bogaerts H. Ue1em A. Andre FE. Submitted for publication.
300
KOTAVIKUS INFECTIONS ANU THEIK PKEVENTION
~y
VACCINATION
TIMO VESIKAKI Uepartment of Clinical Sciences, University of Tampere, 33520 Tampere, Finland KOTAVIKUS INFECTIUNS Kotavirus infections in young children are characterized by acute gastroenteritis with explosive onset, watery diarrhoea, vomiting, fever, and rapid development of dehydration and acidosis (1). Kotavirus diarrhoea often requires hospitalization, and in developed countries rotaviruses are responsible for 50% or more of the hospitalized cases of acute diarrhoea in children (2). Mortality is low in developed countries, but worldwide rotavirus gastroenteritis may be responsible for 500.000 or more deaths annually (3). All rotavirus infections are not associated with gastroenteritis, however, but many are asymptomatic and some may be associated with clinical symptoms other than diarrhoea (4). In Finland, about 50% of the children experienced a rotavirus infection in the first year of life during one epidemic season, and 43% of these infections were associated with diarrhoea (Tables I and II). Severe rotavirus diarrhoea seldom occurs twice in the same child: therefore it is likely that one rotavirus infection induces cross-protection against diarrhoea in subsequent attacks of rotavirus infection. Even a neonatally acqui red asymptomatic rotavi rus infection by a "nursery strain" gives protection against rotavirus diarrhoea, but not infection, for the first 3 years of life (5). RATIONALE FUK KUTAVIKUS VACCINATIUN The goal of rotavirus vaccination would be prevention of severe diarrhoea when children are most susceptible to dehydration, i.e up to the age of 3 years. Prevention of rotavirus infections is not important and may not be possible to achieve with any vaccine. Un the contrary, attacks of natural rotavirus infection in a vaccinated subject may contribute to build-up of immunity while not causing clinical illness (Table I). In Western Europe and USA rotavirus infections mostly follow a clear seasonal pattern with epidemic peak in cold season. The field trials of rotavirus vaccine in Finland have taken advantage of this epidemiologic pattern (6). Infants aged 6 to 12 months were vaccinated before the epidemic period with the purpose of preventing rotavirus diarrhoea for the first two epidemic seasons after that age (7,H). This design could also serve as a model for rotavirus vaccination in developed countries in general. 293
There is a great need for a rotavirus vaccine in the developing countries, but there are also potential problems. Kotavirus diarrhoeas may occur before the age of half a year necessitating early vaccination. Maternal serum antibodies and breast-feeding might then inferfere with the take of rotavirus vaccine. It would also be preferrable to combine oral rotavirus and poliovirus vacci nes, but these vacci ne vi ruses mi ght i nferfere with each other. Ttlese problems are currently being investigated. Altogether prevention of diarrhoeal mortality and morbidity is more complex in developing countries. Many of the 500.000 or so annual deaths from rotavirus diarrhoea are due to dehydration and might be preventable by a rotavirus vaccine. Other deaths result from diarrhoea-mal nutrition-diarrhoea vicious circle, in which rotavirus infections may play some role. The impact of rotavirus vaccine on this morbidity and mortality will be more difficult to assess. KUTAVIKUS VACCINES Several approaches have been proposed for the development of rotavirus vaccines for humans (9). However, so far only attenuated heterologous rotavirus strains have actually been tested as vaccines for children. The KIT 4237 bovine rotavirus vaccine strain was derived from the Nebraska Calf Diarrhea Virus (NCUV) by passaging in primary foetal bovine kidney cells, and the vaccine is produced at the 154th passage level in primary monkey kidney cells suitable for human vaccine production (10). Most of this communication deals with clinical trials of this vaccine. More recently a rhesus monkey rotavi rus vaccine strain KKV-1 (I'IMU-180U6) was introduced as a candidate rotavirus vaccine for humans. This vaccine, developed by A.Z. Kapikian of NIH, is now being evaluated in clinical trials in children. PKUTECTIUN AuAINST KUTAVIKUS DIAKKHUEA
~y
THE KIT 4237 VACCINE
The clinical efficacy of the KIT 4237 vaccine was tested in two double-blind placebo-controlled field trials in Tampere, Finland (7,8). The first trial involved 190 infants aged 8 to 11 months vaccinated in January 1983. In the first epidemic season of rotavirus there were 18 episodes of rotavirus diarrhoea in the 92 placebo recipients vs. only 2 episodes in the 86 vaccine recipients who were followed for the entire season (p < U.UU1, vaccine protection rate 88%). The two cases of rotavirus diarrhoea in the vaccinees occurred in children who failed to develop an ELISA antibody response after
294
post-epidemic sera. There were 5 cases of clinically significant diarrhoea (requiring rehydration therapy) in the KIT 4237 vaccine group vs. 26 in the placebo group (p < 0.001), a protection rate of 81%. One of the 5 cases in the vaccine group had seroconverted after vaccination, the remaining four had not. In addition to cases with frank diarrhoea there were again 8 episodes with mild gastrointestinal symptoms and rotavirus in the stools. Of these 7 were in the vaccine group and only one in the placebo group. The relation of clinical illness and sero-conversion for rotavirus (i.e. primary rotavirus infection) during the epidemic season is presented in Table II. TAHLE II CLINICAL ILLNESS IN KELATION TO KOTAVIKUS INFECTION Occurrence of clinically significant diarrhoea and other gastrointestinal symptoms in rotavirus vaccinees and controls who were seronegative before the rotavirus epidemic season and seroconverted during the season
Group
KIT 4237 Placebo
Seroconversion
Symptomatic
Uiarrhoea
37/5Y (63%) 60/134(45%)
11/37 (30%) 27/60 (45%)
4/37 (11%) 26/60 (43%)
Thus 43% of the detected primary rotavirus infection episodes resulted in clinical diarrhoea in the placebo group. The KIT 4237 vaccine changed this natural history significantly: diarrhoea was present in only 11% of the rotavirus infections in the vaccinees. Even in those cases the diarrhoea was milder with a mean duration of 2.8 days as compared to 4.4 days in the placebo group. The duration of KIT 4237 vaccine-induced protection appears to last longer than over one epidemic season. Table III presents the summary of clinical follow-up during the two epidemic seasons after vaccination for the er.tire group, regardless of serological response.
295
vaccination. In addition to the two cases with clinically overt diarrhoea there were in the vaccine group seven cases of mild gastrointestinal upset associated with rotavirus; no such cases were detected in the placebo group. It appeared that the vaccination had modified the clinical symptoms of rotavirus infection in these cases. There was no protection against rotavirus infection as determined by seroconversion (7). The second field trial involved a larger number of children vaccinated well before the rotavirus epidemic season (8). A total of 347 children received two oral doses of the KIT 4237 vaccine or placebo at one month~s interval in September-Uctober 1983, and post-vaccination sera were collected from 331 in Uecember 1983. After the epidemic, a third serum specimen was collected from 291 children, which indicated good compliance in follow-up. The serological follow-up of the vaccinees is summarized in Table I TAtlLE I SERULUGICAL FULLUW-UP UF RUTAVIKUS VACCINEES Kotavirus ELISA IgG antibodies in 291 children before and after rotavirus vaccination and after an epidemic of rotavirus Vaccine Group KIT 4237 (N=146) Placebo (N=145)
No.(%) Kotavirus seropositive Prevaccination Postvaccination 20 (14%) 11 (8%)
87 (60%) 10 (7%)
Post-epidemic 124 (85%) 70 (48%)
Primarily the majority of the infants were seronegative by IgG ELISA for rotavirus, and 77 of the 146 (53%) seronegative KIT 4237 vaccinees showed seroconversion as compared to only 3 of the placebo recipients (each of the latter also experienced a rotavirus diarrhoea before the collection of the post-vaccination sera). During the epidemic season 6U of the 134 (44%) seronegative children showed seroconversion, indicating either symptomatic (Table II) or asymptomatic rotavirus infection. In the end of the epidemic season a total of 48% of the children were seropositive for rotavirus, as compared to 85% in the KIT 4237 vaccine group. In the vaccine group there were in fact more (63%) seroconversions during the epidemic season (Table II). A possible explanation is that some children may have had a delayed antibody response after vaccination, detectable only after the collection of
296
TAl:ILE II I UUKATIUN UF KOTAVIKUS VACCINE-INUUCEU PKOTECTION Kotavirus diarrhoea in recipients of RIT 4237 rotavirus vaccine and placebo during two epidemic seasons of rotavirus
Group
1st season Jan-May 1984
KIT 4237 (N=168) Placebo (N=160)
2nd season Jan-Apri 1 1985
5
1
26
7
Judged by the above data the vaccine protection rate appears to remain the same for the second year (85%) as for the first season (81%). This suggests that the primary goal of rotavirus vaccination, clinical protection against rotavirus diarrhoea up to the age of 3 years, can be achieved with the KIT 4237 vaccine. The vaccine-induced protection may also cover several rotavirus serotypes. 18 of the rotavirus isolates from cases with clinically significant diarrhoea were serotyped by Ur. TH Flewett, l:Iirmingham, and the results are presented in Table IV. TAl:ILE IV PROTECTION AGAINST KOTAVIKUS SEKOTYPES Cases of rotavirus diarrhoea associated with three different serotypes of human rotavirus in the recipients of the KIT 4237 vaccine and placebo
Human rotavirus serotypes 2 3 Total
Group
1
KIT 4237 Placebo
3
o
o
3
11
2
2
15
The apparent heterotypic (and heterosubgroup) protection induced by the RIT 4237 vaccine raises questions on the protective mechanisms after rotavirus vaccination. These questions remain largely unanswered at the moment. Clearly,
297
serum antibodies (ELISA or neutralizing antibodies) may not be the only protective factor or may not even playa significant role in protection. ENHANCEMENT UF VACCINE TAKE While the significance of serum rotavirus antibodies in protection remains questionable the serological response to vaccination can nevertheless be used as an indicator of vaccine "take". A series of experiments have been carried out to study the effect of feeding on the take rate of KIT 4237 vaccine at different dose levels. It was first discorered that the vaccine virus was labile at pH 3 and below; consequently it was easily destroyed after oral vaccination in the acid conditions of the stomach, but apparently protected by milk feeding before vaccination (II). The effect of milk formula feeding on the serological response to rotavirus vaccine is illustrated in Table V. TA~LE V DOSE KESPUNSE TU KUTAVIRUS VACCINE
Serum neutralizing antibody response in 4-6 month-old infants who received a single oral KIT 4237 vaccination immediately after milk formula feeding or after 2 hours'fasting (12)
KIT 4237 Vaccine titer
No. (%l with response Formula-fed Unfed
10. 8 • 3
14/14 (lUO%)
5/8 (63%)
10 7• 2
10/14 (71%)
4/9 (44%)
106• 3
2/12 (15%)
2/7 (29%)
The conclusion from the above study was that the RIT 4237 vaccine should be administered together with an acid neutralizing substance such as milk formula. Further, the vaccine dose should be of the order of 108 tissue culture infective doses, as was used in the clinical trials presented previously. The possible (inhibitory) effect of breast milk on rotavirus vaccination remains to be studied. This question is of great importance, since breast
298
feeding is highly recommendable in the apparent target group of rotavirus vaccination, infants aged 0 to 6 months. Uur preliminary experience suggests that breast feeding may not be inhibitory for rotavirus vaccine in children over 6 months of age, but may interfene with the vaccine take in newborns. CONCLUS IONS The ~IT 4237 attenuated bovine rotavirus vaccine appears a serious candidate for rotavirus vaccination in humans. The vaccine does not cause any appreciable symptoms in children (7,13), but oral vaccination leads to a subclinical gastrointestinal infection characterized by a low degree of virus excretion (13) and still a high serological response rate of 75-100%. The vaccine induces protective immunity against rotavirus diarrhoea for at least two years, and the protection may cover more than one serotype of rotaviruses. The RIT 4237 vaccine appears sufficiently were established for a general rotavirus vaccination in developed countries. A vaccination of infants of the age of 6 months would prevent about 75% of all cases of winter diarrhoea (7,8), and therefore lead to significant reduction in hospitalization and treatment costs. A cost-benefit analysis for rotavirus vaccine remains to be done pending formal price quotation. It seems that the dose level will have to be as high (108 ) as can easily be produced in the present cell substrate. In any case the vaccine should be affordable for developed countries. It is not known if the ~IT 4237 vaccine will be efficacious in the conditions of developing countries, and further studies one required before rotavirus vaccination will be available for the third world.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8.
Maki M (1~81) Acta Paediatr Scand 70: 107-113 Steinhoff M~ (1980) J Pediatr 96: 611-622 ~utler Te (1984) J Uiar Uis ~es 2: 137-141 Champsaur H, Henry-Amar M, (joldszmidt U et al (1984) J Infect Dis 149: 675-682 ~ishop RF, ~arnes (jL, Cipriano E, Lund E (1983) N Engl J Med 909: 72-76 Vesikari T, Maki 1"1, Isolauri E (1983) Uevelop ~iol Standard 53: 229-236 Vesikari T, Isolauri E, U-Hondt E, Uelem A, Andre FE, Lissis 6 (1984) Lancet i: 977-981 Vesikari T, Isolauri E, Uelem A et al (1985) J Pediatrics, in press
299
9. 10. 11. 12.
Kapikian AZ. Wyatt IHi. Greenberg HB et a1 (1980) Hev Infect Uis 2: 459-469 De1em A. Lobmann M. Zygraich N (1984) J Bio1 Standard 4: 443-445 Vesikari T. Iso1auri E. U-Hondt E. Ue1em A. Andre FE (1984) Lancet ii: 7UU Vesikari T. Huuska T. Bogaerts H. Ue1em A. Andre FE. Submitted for publication.
300