Journal of Infection (I99I) zz, II9"-I28
REVIEW The status of rotavirus
v a c c i n e s i n I99O
I. E. Haffejee*
Department of Paediatrics and Child Health, Faculty of Medicine, University of Natal, Durban, South Africa Accepted for publication 28 September I99o Summary The status of rotavirus (RV) vaccines in I99o is reviewed with particular reference to the range of RV strains which infect human beings as well as the antibody response and immunity to naturally acquired RV infections. The requirements for an ideal vaccine are stated and the various approaches towards developing RV vaccines are described. Results of various field trials are given and finally important questions are posed which remain to be addressed if success in producing an ideal vaccine is to be achieved.
Introduction It has been estimated that about 870000 children die annually f r o m rotavirus (RV) diarrhoea worldwide, m o s t deaths being in developing countries. 1 T h e W o r l d H e a l t h Organisation ( W H O ) estimate o f the total n u m b e r of deaths f r o m gastro-enteritis (GE) in children below 5 years of age for the year I98O was 4"6 million. 2 A b o u t 20-4o % of these are t h o u g h t to be RV-relatedfl A n effective RV vaccine m i g h t avert between half and one million deaths in children annually.
Range o f RV strains which infect human beings T h e rotavirus genome consists of I I segments of d o u b l e - s t r a n d e d R N A enclosed in a double-shelled capsid. T h e r e are three major forms of serological classification o f RVs : (a) reactions of antisera against the major capsid antigen VP6 distinguish at least two subgroups;4-6 VP6 also comprises the c o m m o n RV group antigen which is c o m m o n to h u m a n as well as to animal R V s ; 4 (b) neutralisation tests or monoclonal a n t i b o d y reactions against the outer capsid proteins VP7 and VP4 distinguish six serotypes n u m b e r e d sequentially I - 6 of which the first four are m o s t often e n c o u n t e r e d ; 4-1° (c) polyacrylamide gel electrophoresis permits separation of the I I R N A segments of the genome, so that, according to the mobilities o f the i o t h and I i t h segments, the differences in migration patterns (known as electropherotypes) m a y be subclassified into * Address correspondence to: Dr I. E. Haffejee, Department of Paediatrics and Child Health, University of Natal, P.O. Box I7O39, Congella 4oi3, South Africa. oi63-4453/9I/o2oi t 9 + Io $03.00/0
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'long', ' s h o r t ' , and ' super-short' strains. A'9.11.12 Both in cell-cultures coinfected with two strains, as well as in nature, cross-over or reassortment of some gene-segments from one RV strain with corresponding ones from another may take place, thereby resulting in reassortment strains each of which has its own pathogenic potential. Different electropherotypes often circulate at the same time within a community. Furthermore, the virus population in a given geographical area changes with time. la' 14 Similar changes in prevailing serotypes have also been recorded, so that there is considerable diversity among human RVs. 15
A n t i b o d y r e s p o n s e a n d i m m u n i t y to RV i n f e c t i o n s
Infection with RV evokes both a local intestinal and a serum antibody response. Intestinal antibodies appear early: RV-specific I g M and I g G may be detected in duodenal secretions in the acute phase of RV GE, persist during convalescence and disappear by 6 - i 2 months. 1~-1sAnti-RV IgA is found in the faeces of infected persons from the fourth day of infection for up to 6 months. 17'18 Faecal anti-RV IgA titres accurately represent the intestinal immune response since they correlate positively with titres in duodenal secretions. 19.20 Serum anti-RV I g M appears early in the acute phase of a primary infection, usually between 5 and 9 days, 16' 17 and disappears within 5 weeks.~l Serum IgA also appears during the first week, peaks at around 2 weeks and persists for at least 4 months. 20 Concentrations of serum and intestinal RV IgA correlate well in infants, children and adults. 19' 22 This may not be the case in neonates who have been found to evoke a mucosal (salivary) IgA response without a concomitant serum antibody response. 2a Beyond the neonatal period, therefore, faecal RV IgA may be useful in assessing immunity to RV infection but only up to about 6 months after infection. Even so, Bernstein et a l . , 24 found that pre-existing faecal antibodies failed to protect against infection. Serum RV I g G titres rise slowly between the first and fourth weeks, are very high 30-45 days after infection, and persist for I 2 - I 5 months. 16' 17.21 Serum neutralising antibodies to RV make their appearance within 2 weeks of infection and are in general specific for the infecting serotype. 25'26 Heterotypic responses to other serotypes, however, have also been reported and such responses appear to depend on the infecting serotype : infection with serotypes I or 2 elicit homotypic responses only, whereas, after infection by serotype 3, neutralising antibodies to serotypes I and 4, as well as to serotype 3, app ear.2~' 27-29 T h e role of antibodies in protecting against RV infection is unclear. Mucosal antibodies certainly do appear to be protective. For example, human milk with an anti-RV IgA concentration >~ I80 g/l, bovine colostrum rich in RV antibodies, and orally administered gamma-globulin containing RVantibodies have all been shown to afford significant passive protection, a°-a2 On the other hand, there was no correlation between pre-existing faecal anti-RV IgA concentrations and protection against infection in adult volunteers.24 It does appear, however, that resistance to clinical disease correlates well with
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homotypic anti-RV secretary IgA concentrations as well as with homotypic neutralising serum antibody titres >~ I28. 25'33 In most vaccine trials to date titres of serum neutralising antibodies have been used as a measure of immunogenicity. 3~-37
R e q u i r e m e n t s for an ideal v a c c i n e
An ideal vaccine should induce substantial, long-lasting immunity against RV diarrhoea in young infants following a single oral dose. It should be administered at 2-3 months of age, since, despite the highest prevalence of the disease in the 6-24 month age group in developed countries, severe rotaviral diarrhoea is found in m u c h younger infants in some third world countries) 8-41 If, as appears probable, multiple doses are required, it would be convenient to combine the vaccine with oral poliomyelitis vaccine, a practice which would ensure greater compliance. Thus, it would be of practical importance to know whether the two vaccines can be given profitably in combination or whether they would interfere with each other as far as immunogenicity is concerned. This question is addressed later in this article. A good vaccine would have to protect against multiple RV serotypes.
A p p r o a c h e s used for r o t a v i r u s v a c c i n e d e v e l o p m e n t
Theoretically, several strategies might be employed for developing vaccines against rotavirus, as follows. (a) H u m a n and animal group A RVs share a common group antigen VP-6 situated in the inner core of the RV particle. 4'42'43 Therefore, cell cultureadapted animal rotavirus could be used as live, attenuated strains in a vaccine. Attenuation implies that the virus is rendered non-pathogenic by multiple passages through cell culture but retains its immunogenic properties. 33 (b) T h e VP-7 outer capsid protein (the major neutralisation antigen) of h u m a n rotavirus (HRV) can be incorporated into an animal RV by coinfecting cell cultures with both a h u m a n and an animal strain. 43'44 T h e resulting 'reassortant' strain might then be used as a vaccine. (c) It is well-known that h u m a n neonatal RV infections are, in the main, asymptomatic or very mild, being partly accounted for by natural attenuation of the ' n u r s e r y ' strains by virtue of a modification in the VP-4 outer capsid protein. 45'46 Thus, natural RV strains from asymptomatic neonates might be used as a vaccine. (d) Multiple passage of h u m a n RV in cell culture results in the production of naturally attenuated strains which may be used as candidate vaccines. 43,47.48 In practice, all four strategies have been tried in attempts to develop candidate live, attenuated oral RV vaccines, with varying results. Virulence in experimental animals is usually gauged by administrating oral HRV (which is normally pathogenic to n o n - i m m u n e newborn calves) to newborn calves which have earlier been ' i m m u n i s e d ' in utero by the candidate vaccine and which have not been fed their mother's colostrum. T h e y are then observed for development of gastro-enteritis. If avirulent by this test, the vaccine is further
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evaluated serially in adult volunteers with anti-RV antibody, in seronegative adults and then in progressively younger persons, first in seropositive and then (if avirulent) in seronegative subjects33 R o t a v i r u s v a c c i n e s u s e d in t r i a l s U s e o f a n i m a l R V s as v a c c i n e s in h u m a n b e i n g s
Experiments in colostrum-deprived piglets showed that cross-protection is afforded by a bovine strain R I T 4237 against h u m a n strains. 49 Two bovine vaccines, the R I T 4237 and the WC 3, as well as the simian strain M M U 18oo6, have been used in field trials in h u m a n beings35' 36.50-5~These are all live attenuated vaccines which have undergone multiple passages in cell culture: I47 passages in the case of R I T 4237 but only I2 in the case of WC 3 and I6 in the case of M M U 18oo6. (a) Bovine R I T 4237 vaccine
Initial placebo-controlled trials of this vaccine, involving more than 3oo infants in Finland, gave a protection rate of over 80 % in 6 - i 2 month oldinfants,35, 36 the response being the same in both those breast-fed and bottlefed. 56 Neutralisation of gastric acidity by administering the vaccine with milk increased the seroconversion rate to 90 % F while protection lasted for at least one epidemic season. However, because of its ineffectiveness in over 400 infants in Africa 58' 59 and in Apache Indians in the U.S.A33--probably due to viral interference--the R I T 4237 has recently been withdrawn by the manufacturers. (b) Bovine W C 3 vaccine This vaccine, derived from a different bovine RV, is used at a five-fold lower concentration and after fewer passages in cell culture than the R I T 4237 vaccine. It gave a neutralising antibody response in 95 % of N o r t h American infants aged 5-I I months. Its efficacy appears to be independent of previous antibody status or antacid treatment of the vaccinees3 ° In a more recent trial involving IO4 infants in Philadelphia, U.S.A., its efficacy was Ioo % against severe (and 76 % against all) RV diarrhoea31 It is currently being evaluated in Israel and the Central African Republic33 T h e mechanism of protection given by the bovine vaccines is unknown. T h e major cross-reactive antigen between bovine and h u m a n RVs is the group-specific inner capsid protein VP-6 which is not involved in the induction of neutralising antibodies.
I8OO6 vaccine Preliminary trials of this vaccine (also known as the RRV-I vaccine) in adults with low antibody titres showed it to be well-tolerated and highly immunogenic, with a seroconversion rate of over 8o%. 5~'6° Significant protection was provided in a small double-blind randomised placebocontrolled field trial in the U.S.A3 ~ In addition, Gothefors et al., 61 showed that it gave Ioo % protection against severe, and 48 % protection against all, RV diarrhoea in a trial involving IO6 infants in Sweden. Flores et al., 54 (c) Rhesus M M U
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performed a similar trial in 247 infants in two low-income communities in Venezuela observed for a period of I year and obtained Ioo % protection against severe RV and 64 % against all RV diarrhoea. In infants between I and 5 months of age the efficacy was 93 %. Studies in Finland and the U.S.A., however, have not confirmed these findings, the protection rate in these varying from o-38 %.53' 62 One explanation for this discrepancy is the fact that, in these later trials, most episodes of diarrhoea were due to serotype r RV, to which the M M U I8OO6 (or RRV-I) is not related by the viral antigen VP-7. By contrast, in the Venezuelan trial, the commonest causative agent was serotype 3 RV which is closely related antigenically to RRV-I by VP-7. T h e seroconversion rate of 8o % found earlier in adults by Kapikian et al., 6° has been confirmed in 5o children aged 3-~z months in T e n n e s s e e ) ~ T h e main adverse reaction encountered with the use of this vaccine in doses of Io 5 or IO6 plaque-forming units (PFU) is fever in 3o-7o% of the vaccinees. T h e Venezuelan study cited above employed a dose of Io 4 P F U but makes no mention of fever or other untoward effects) 4 Reassortant RV vaccines
(a) A bovine-human reassortant vaccine
This vaccine designated WI79-9, the bovine WC 3 rotavirus into which the VP-7 protein from serotype I h u m a n RV has been incorporated, is currently being evaluated in the U.S.A. It is hoped that I o o % protection against diarrhoea caused by the h u m a n serotype I RV is afforded. 53 (b) Rhesus-human reassortant vaccines
Here the VP-7 antigens of h u m a n RVs serotypes I and 2, respectively, have been incorporated into rhesus rotavirus. In Finland 88 % and in the U.S.A. 67 % protection against H R V serotype I diarrhoea has been r e p o r t e d ) 3 (c) Combined rhesus-human reassortant vaccine
A quadrivalent reassortant vaccine combining serotype 3 rhesus rotavirus with h u m a n serotypes I, 2 and 4 has undergone a small field trial in Venezuela. About 75% of 45 recipients showed serum IgA antibody responses; neutralising antibody responses to serotypes I-4 were found in only 4o % of vaccinees. Febrile reactions were reported in 3o % of them but long-term results are as yet unavailable for assessing protection (if any) against diarrhoea. 3v Neonatal human
RV strain vaccines
T h e rotaviral protein VP-4 is altered in the neonatal or ' n u r s e r y ' RV strains, resulting in very mild or asymptomadc natural infections in the corresponding age-group. Babies acquiring such infections when neonates are later partially protected against RV diarrhoea (but not necessarily against RV infection) as shown in a long-term study in Australia. 45 On the basis of this, a naturally attenuated strain of H R V with an altered VP-4 has been developed as a candidate vaccine, named M37, in the U.S.A. ; it cross-reacts with serotypes i and 4 .53 Preliminary results in 22 infants have shown a 50 % serum IgA
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response, a 64 % neutralising antibody response and transient fever in 20 % recipients but information on protection against diarrhoeal illness is so far unavailable. 37 A t t e n u a t e d h u m a n RV v a c c i n e
Limited work on young adult volunteers with a h u m a n strain (the HRV 5 derived from the Wa strain), attenuated by passage in cell culture, gave a seroconversion rate of 6o % without any adverse reactions. 63 Thus, to summarise, of the animal vaccines, one rhesus and two bovine RV vaccines have so far undergone field trials. One bovine vaccine had to be withdrawn due to insufficient efficacy, mainly in third world situations. Efficacy of the rhesus M M U 18006 vaccine has varied in different geographical locations, mainly because of variability in the serotype of the wild virus, the vaccine being most effective against serotype 3 h u m a n rotavirus. T h e single animal RV vaccine which has shown most promising results up to now has been the bovine WC 3 with an efficacy around 9O-lOO %. This seems to have been independent of previous antibody status or antacid treatment of the vaccinees, although field trials larger than those hitherto performed are clearly indicated. A human-bovine reassortant vaccine, WI79-9, appears to show good efficacy but its evaluation is still in the early stages. Rhesus-human reassortant vaccines have shown variable results in early trials. A polyvalent or multiserotype rhesus-human reassortant vaccine, currently under evaluation, may provide the answer as long as inter-serotype interference in antibody response does not take place although, at present, there appears to be an unacceptably high rate of febrile reactions. It is too early to comment on a naturally attenuated h u m a n 'neonatal' RV vaccine. Questions which need to be addressed include the following. (i) Is there a need for fasting before oral vaccination ? (ii) Can a vaccine be given with an ordinary feed ? Most vaccines at present have to be given with a buffered feed. Further work to simplify the procedure is necessary if mass vaccination is to become feasible. (iii) Would anti-RV antibodies or other anti-RV factors in breast milk interfere with the 'take' in breast-fed infants ? (iv) What would be the duration of immunity ? (v) Are multiple doses necessary or would protective concentrations of antibody be sustained in later life by infections with wild strains ? (vi) Could a rotavirus vaccine be administered together with routine oral polio vaccine ? Simultaneous administration of the R I T 4237 vaccine with oral polio vaccine caused a significant reduction both in the number of vaccinees with an anti-RV antibody response (from 74-33 % vaccinees) and in the mean neutralising antibody titre to RV (from 351-193) but the response to the polio vaccine was not affected.64 In another trial, however, infants infected with entero-viruses at the time of receiving the WC3 vaccine failed to show a neutralising antibody response, thereby suggesting viral interference, s° On the other hand, live RV vaccine does not appear to interfere with the response to live oral polio vaccine. 64'65 (vii) Can a single vaccine afford protection against the multiple serotypes, subgroups and electropherotypes of RV ? Since the present answer appears to
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b e n o , this q u e s t i o n r e q u i r e s u r g e n t a t t e n t i o n in t h e l i g h t o f t h e k n o w n c o m p l e x d i v e r s i t y o f r o t a v i r u s e s . 66 (viii) S h o u l d live v a c c i n e s b e u s e d in i m m u n o c o m p r o m i s e d i n f a n t s s u c h as those with human immunodeficiency virus (HIV) infections, Hodgkin's d i s e a s e , l y m p h o m a , l e u k a e m i a , or t h o s e r e c e i v i n g r a d i a t i o n t h e r a p y o r p r o l o n g e d t r e a t m e n t w i t h c o r t i c o - s t e r o i d s ? A t p r e s e n t t h e a n s w e r is no. A l t h o u g h a n t i - R V I g G h a s b e e n d e t e c t e d in t h e s e r u m o f IO i m m u n o d e f i c i e n t children without diarrhoea and who had had prior therapy with gammag l o b u l i n , t h e titres w e r e m u c h l o w e r t h a n t h o s e in h e a l t h y c h i l d r e n . 67 M o r e e x t e n s i v e field trials i n v o l v i n g l a r g e r p o p u l a t i o n s a n d i n c l u d i n g n e o n a t e s n e e d to b e d o n e f o r a t h o r o u g h a n d c o m p r e h e n s i v e e v a l u a t i o n . H a p p i l y , m a n y a r e a l r e a d y u n d e r w a y in v a r i o u s p a r t s o f t h e w o r l d . (I am extremely grateful for the advice, guidance and constructive criticisms of Professor A. Moosa, former H e a d of the D e p a r t m e n t of Paediatrics, and of D r I. Windsor, D e p u t y Director, D e p a r t m e n t of Virology, Faculty of Medicine, University of Natal, D u r b a n . Financial assistance from the South African Medical Research Council is gratefully acknowledged.) References I. Ho M-S, Glass RI, Pinsky PF, Anderson LJ. Rotavirus as a cause of diarrheal morbidity and mortality in the United States. J Infect Dis 1988 : I58 : I 112-1116. 2. Snyder JD, Merson MH. The magnitude of the global problem of acute diarrhoeal disease : a review of active surveillance data. Bull W H O 1982; 6o: 6o5-613. 3. DeZoysa I, Feachem RG. Interventions for the control of diarrhoeal diseases amongyoung children: rotavirus and cholera immunization. Bull W H O 1985; 63:569-583 • 4. Flores J, Nakagomi O, Nakagomi T et al. The role of rotaviruses in pediatric diarrhea. Pediatr Infect Dis J 1986; 5: $53-$62. 5. Kapikian AZ, Cline WL, Greenberg HB et al. Antigenic characteristics of human and animal rotaviruses by immune adherence hemagglutination assay (IAHA): evidence for distinctness of IAHA and neutralization antigens. Infect Immun 1981; 33: 415-425. 6. Thouless ME, Beards GM, Ftewett TH. Serotyping and subgrouping of rotavirus strains by the ELISA test. Arch Virol 1982 ; 73: 219-23o. 7. Flewett TH, Thouless ME, Pilford JN, Bryden AS, Candeias JAN. More serotypes of human rotavirus. Lancet 1978; ii: 632. 8. Hoshino Y, Wyatt RG, Greenberg HB et al. Serotypic similarity and diversity of rotaviruses of mammalian and avian origin as studied by plaque reduction neutralization. J Infect Dis 1984; 149: 694-702. 9- Tursi JM, Albert MJ, Bishop RF. Production and characterization of neutralizing monoclonal antibody to a human rotavirus strain with a human rotavirus strain with a 'super short' RNA pattern. J Clin Microbiol 1987; 25: 2426-2427. IO. Clark HF, Hoshino Y, Bell L M et al. Rotavirus isolate W I 6 I representing a presumptive new human serotype. J Clin Microbiol 1987; 25: 1757-1762. i i. Kalica AR, Garon CF, Wyatt RF et al. Differentiation of human and calf reoviruslike agents associated with diarrhea using polyacrylamide gel electrophoresis of RNA. Virology 1976; 74: 86-92. 12. Beards GM. Polymorphism of genomic RNAs within rotavirus serotypes and subgroups. Arch Virol 1982 ; 74: 65-7o. 13. Rodger SM, Bishop RF, Birch C et al. Molecular epidemiology of human rotaviruses in Melbourne, Australia from 1973 to 1979 as determined by electrophoresis of genome ribonucleic acid. J Clin Microbiol 1981 ; 13: 272-278. 14. Tam JS, Bojian Z, Yongkai Y e t al. Occurrence of rotaviruses in Guangzhou and Hong Kong. J Infect Dis 1988; 157: 357-363.
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I5. Urasawa S, Urasawa T, Taniguchi K et al. Survey of human rotavirus serotypes in different locales in Japan by enzyme-linked immunosorbent assay with monoclonal antibodies. J Infect Dis I989; I6O: 44-5 I. I6. Davidson GP, Hogg RJ, Kirubakaran CP. Serum and intestinal immune response to rotavirus enteritis in children. Infect Immun I983 ; 40: 447-452. 17. Hjelt J, Grauballe PC, Andersen T,, Schiotz PO, Howitz P, Krasilnikoff PA. Antibody response in serum and intestine in children up to six months after a naturally acquired rotavirus gastroenteritis. J Paediatr Gastroemerol Nutr I986; 5: 74-8o. i8. Riepenhoff-Talty M, Bogger-Goren S, Li P, Carmody PJ, Barrett HJ, Ogra PL. Development of serum and intestinal antibody response to rotavirus after naturally acquired infection in man. J Med Virol r 9 8 I ; 8: 215-222. 19. Bernstein D I , McNeal M M , Schiff G M , W a r d RT,. Induction and persistence of local rotavirus antibodies in relation to serum antibodies. J Med Virol I989; 2 8 : 9 0 - 9 5 . 20. Grimwood K, L u n d JCS, Coulson BS, Hudson IT., Bishop RF, Barnes GL. Comparison of serum and mucosal antibody responses following severe acute rotavirus gastroenteritis in young children. J Clin Microbiol I988; 26: 732-738. 2I. Orstavik I, Haug K W . Virus-specific I g M antibodies in acute gastroenteritis due to a Reovirus-like agent (Rotavirus). Scand.7 Infect Dis I976; 8: 237-240. 22. W a r d RT,, Bernstein D I , Shukla R et al. Effects of antibody to rotavirus on protection of adults challenged with a human rotavirus..7 Infect Dis I989; x59: 79-88. 23. Jayashree S, Bhan M K , K u m a r R et al. Serum and salivary antibodies as indicators of rotavirus infection in neonates..7 Infect Dis I988; I58: I I I 7 - I I 2 O . 24. Bernstein D I , Ziegler JM, W a r d RT,. Rotavirus fecal IgA response in adults challenged with human rotavirus..7 Med Virol I986; 20: 297-3o4. 25. Chiba S, Yokoyama T, Nakata S e t al. Protective effects of naturally acquired homotypic and heterotypic rotavirus antibodies. Lancet I986; ii: 417-42I. 26. Zheng B-J, Hans S-X, Yan Y - K et al. Development of neutralizing antibodies and group A common antibodies against natural infections with human rotavirus. J Clin Microbiol I988 ; 26: I506--I512. 27. Kapikian AZ, Wyatt RG, T,evine M M et al. Oral administration of human rotavirus to volunteers : induction of illness and correlates of resistance..7 Infect Dis I983 ; I47 : 95-IO6. 28. Clarke H F , Dolan K T , Horton-Slight P, Palmer J, Plotkin SA. Diverse serologic response to rotavirus infection of infants in a single epidemic. Pediatr Infect Dis I985; 4: 626-63I. 29. German G, Battaglia M, Milenesi G, Passarani N, Percivalle E, Cattaneo E. Serotyping of cell culture-adapted subgroup 2 human rotavirus strains by neutralization. Infect Immun I984; 43 : 722-729 • 30. McLean B, Homes IH. Effects of antibodies, trypsin, and trypsin inhibitors on susceptibility of neonates to rotavirus infection..7 Clin Microbiol I98I ; I3 : 22-29. 3 I. Davidson GP, Whyte PBD, Daniels E et al. Passive immunisation of children with bovine colostrum containing antibodies to human rotavirus. Lancet I989; ii: 7o9-712. 32. Barnes G L , Doyle L W , Hewson P H et al. A randomised trial or oral gamma globulin in low birth weight infants infected with rotavirus. Lancet 1982; i: 137 I - 1373. 33. Kapikian AZ, Wyatt R G , Greenberg HB et al. Approaches to immunization of infants and young children against gaestroenteritis due to rotaviruses. Rev Infect Dis r98o; 2: 459-46934. Vesikari T, Isolauri E, Delem A, D ' H o n d t E, Andre FE. Immunogenicity and safety of live oral attenuated bovine rotavirus vaccine strain R I T 4237 in adults and young children. Lancet I983; ii: 8 o 7 - 8 I I . 35. Vesikari T , Isolanri, E, D ' H o n d t E, Delem A, Andre FE, Zissis G. Protection of infants against rotavirus diarrhoea by R I T 4237 attenuated bovine rotavirus strain vaccine. Lancet 1984; i: 977-98I. 36. Vesikari T , Isolauri E, Delem A e t al. Clinical efficacy of the R I T 4237 live attenuated bovine rotavirus vaccine in infants vaccinated before a rotavirus epidemic..7 Pediatr I985 ; IO7: I89-194. 37. Flores J, Perez-Schael I, Blanco M e t al. Comparison of reactogenicity and antigenicity of M37 rotavirus vaccine and rhesus-rotavirus-based quadrivalent vaccine. Lancet I99O; 336: 330-333 •
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38. Muchinik GR, Grinstein S, Plaza A. Rotavirus infection in children hospitalised for diarrhoea in Argentine. Annals Trop Paediatr 1981; I : I67-I73. 39. Mata L, Simhon A, Paditla R et al. Diarrhea associated with rotaviruses, enterotoxigenic Escherichia coli, Campylobacter, and other agents in Costa Rican children, i976-I98 I. A m J Trop Med Hyg I983; 3 2 : I 4 6 - I 5 3 • 40. Paul MO, Paul BD. Rotavirus infection among children in hospital in Nigeria. J Infect I986; IZ: 39-47. 4I. Haffejee IE, Moosa A. Rotavirus studies in Indian (Asian) South African infants with acute gastro-enteritis: I. Microbiological and epidemiological aspects. Annals Trop Paediatr I99o; Io: I65-I72. 42. Flewett T H , Bryden AS, Davies H, Woode G N , Bridger JC, Derrick JM. Relation between viruses from acute gastroenteritis of children and newborn calves. Lancet I974; ii: 6i-63. 43. Kapikian AZ, Flores J, Hoshino Y e t al. Rotavirus: the major etiologic agent of severe infantile diarrhea may be controllable by a ' Jennerian' approach to vaccination. J Infect Dis I986; x53: 815-822. 44. Greenberg HB, Kalica AR, Wyatt RG, Jones RW, Kapikian AZ, Chanock RM. Rescue of noncultivatable human rotavirus by gene reassortment during mixed infection with ts mutants of a cultivatable bovine rotavirus. Proc Natl Acad Sci U S A I98I ; 78: 420-424. 45. Bishop R F , Barnes G L , Cipriani E, L u n d JS. Clinical immunity after neonatal rotavirus infection. A prospective longitudinal study in young children. New Engl J Med I983 ; 3 o 9 : 72-76. 46. Hoshino Y, Wyatt R G , Flores J, Midthun K, Kapikian AZ. Serotypic characterization of rotaviruses derived from asymptomatic human neonatal infections. J Clin Microbiol I985 ; 2 I : 425-430. 47. Wyatt R G , James H D Jr, Pittman A L et al. Direct isolation in cell culture of human rotavirus and their characterization into four serotypes. J Clin Microbiol I982 ; I8 : 31 0-31748. Ward RL, Knowlton DS, Pierce MJ. Efficiency of human rotavirus propagation in cell culture. J Clin Microbiol I984; I9 : 748-753. 49. Zissis G, Lambert JP, Marbehant P e t al. Protection studies in colostrum-deprived piglets of a bovine rotavirns vaccine candidate using human rotavirus strains for challenge. J Infect Dis I983; I48: IO6I-Io68. 50. Clark H F , Furukawa T, Bell L M , Offit PA, Perrella PA, Plotkin SA. Immune response of infants and children to low-passage bovine rotavirus (strain WC3). A m J Dis Child I986; I4O : 350-356. 5 I. Clark H F , Borian FE, Bell L M , Modesto K, Gouvea V, Plotkin SA. Protective effect of WC3 vaccine against rotavirus diarrhea in infants during a predominantly serotype i rotavirus season. J Infect Dis I988; I58: 570-586. 52. Losonsky GA, Rennels MB, Kapikian AZ et al. Safety, infectivity, transmissibility and immunogenicity of rhesus rotavirus vaccine ( M M U 18006) in infants. Pediatr Infect Dis 5 : 25--29 . 53- W o r l d Health Organisation. Diarrhoeal Disease Control Programme. Rotavirus vaccines. W H O publication No. W H O / C D D / R E S / 8 9 . I I . Geneva, I989. 54. Flores J, Perez-Schael I, Gonzalez et al. Protection against severe rotavirus diarrhoea by rhesus rotavirus vaccine in Venezuelan infants. Lancet I987; i: 882-884. 55. Wright PF. Tajima T , Thompson J, Kokubun K, Kapikian A, Karzon D T . Candidate rotavirus vaccine (Rhesus rotavirus strain) in children: an evaluation. Pediatrics I987; 8o: 473-480. 56. Vesikari T, Ruuska T, Delem A, Andre FE. Oral rotavirus vaccination in breast- and bottle-fed infants aged 6 to I2 months. Acta Paediatr Scand I986 ; 75: 573-57857. Vesikari T, Isolanri E, D ' H o n d t E, Delem A, Andre FE. Increased ' t a k e ' rate of oral rotavirus vaccine in infants after milk feeding. Lancet x984; ii: 7oo. 58. De Mol P, Zissis G, Butzler J-P, Mutwewingabo A, Andre FE. Failure of live, attenuated oral rotavirus vaccine. Lancet I986; ii: Io8. 59. Hanlon P, Hanlon L, March V e t al. Trial of an attenuated bovine rotavirus vaccine ( R I T 4237) in Gambian infants. Lancet I987; i: I342-I345 . 60. Kapikian AZ. Midthun K, Hoshino Y e t al. Rhesus rotavirus: a candidate vaccine for
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61. 62. 63. 64. 65. 66. 67.
I.E. HAFFEJEE prevention of human rotavirus disease. In: Lerner RA, Chanock RM, Brown F, Eds. Vaccines 85. Molecular and chemical basis of resistance to parasitic, bacterial and viral disease. Cold Spring Harbor, NY: Cold Spring Harbour Laboratory, 1985: 357-367. Gothefors L, Wadell G, Juto P, Taniguchi K, Kapikian AZ, Glass RI. Prolonged efficacy of rhesus rotavirus vaccine in Swedish children. J Infect Dis I989; I59: 753-757. Christy C, Madore HP, Pichichero ME et al. Field trial of rhesus rotavirus vaccine in infants. Pediatr Infect Dis J I988; I: 645-650. Kapikian AZ, Wyatt RG, Levine MM et al. Studies in volunteers with human rotavirus. Dev Biolog Stand 1983 ; 53: 2o9-218. Vodopija I, Baklaic Z, Vlatkovic R et al. Combined vaccination with live oral polio vaccine and the bovine rotavirus R I T 4237 strain. Vaccine 1986; 4: 233--236. Hanlon P, Hanlon L, Marsh V e t al. Serological comprisons of approaches to polio vaccination in the Gambia. Lancet 1987; i: 8oo-8ol. Editorial. Puzzling diversity of rotaviruses. Lancet 199o; 335: 573-575. Ushijima H, Honma H, Ohnoda et al. Detection of antirotavirus IgG, IgM, and IgA antibodies in healthy subjects, rotavirus infections and immunodeficiencies by immunoblotting. J Med Virol I989; 27: 13-18.
REVIEW The status of rotavirus
v a c c i n e s i n I99O
I. E. Haffejee*
Department of Paediatrics and Child Health, Faculty of Medicine, University of Natal, Durban, South Africa Accepted for publication 28 September I99o Summary The status of rotavirus (RV) vaccines in I99o is reviewed with particular reference to the range of RV strains which infect human beings as well as the antibody response and immunity to naturally acquired RV infections. The requirements for an ideal vaccine are stated and the various approaches towards developing RV vaccines are described. Results of various field trials are given and finally important questions are posed which remain to be addressed if success in producing an ideal vaccine is to be achieved.
Introduction It has been estimated that about 870000 children die annually f r o m rotavirus (RV) diarrhoea worldwide, m o s t deaths being in developing countries. 1 T h e W o r l d H e a l t h Organisation ( W H O ) estimate o f the total n u m b e r of deaths f r o m gastro-enteritis (GE) in children below 5 years of age for the year I98O was 4"6 million. 2 A b o u t 20-4o % of these are t h o u g h t to be RV-relatedfl A n effective RV vaccine m i g h t avert between half and one million deaths in children annually.
Range o f RV strains which infect human beings T h e rotavirus genome consists of I I segments of d o u b l e - s t r a n d e d R N A enclosed in a double-shelled capsid. T h e r e are three major forms of serological classification o f RVs : (a) reactions of antisera against the major capsid antigen VP6 distinguish at least two subgroups;4-6 VP6 also comprises the c o m m o n RV group antigen which is c o m m o n to h u m a n as well as to animal R V s ; 4 (b) neutralisation tests or monoclonal a n t i b o d y reactions against the outer capsid proteins VP7 and VP4 distinguish six serotypes n u m b e r e d sequentially I - 6 of which the first four are m o s t often e n c o u n t e r e d ; 4-1° (c) polyacrylamide gel electrophoresis permits separation of the I I R N A segments of the genome, so that, according to the mobilities o f the i o t h and I i t h segments, the differences in migration patterns (known as electropherotypes) m a y be subclassified into * Address correspondence to: Dr I. E. Haffejee, Department of Paediatrics and Child Health, University of Natal, P.O. Box I7O39, Congella 4oi3, South Africa. oi63-4453/9I/o2oi t 9 + Io $03.00/0
© I99I The British Society for the Study of Infection
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'long', ' s h o r t ' , and ' super-short' strains. A'9.11.12 Both in cell-cultures coinfected with two strains, as well as in nature, cross-over or reassortment of some gene-segments from one RV strain with corresponding ones from another may take place, thereby resulting in reassortment strains each of which has its own pathogenic potential. Different electropherotypes often circulate at the same time within a community. Furthermore, the virus population in a given geographical area changes with time. la' 14 Similar changes in prevailing serotypes have also been recorded, so that there is considerable diversity among human RVs. 15
A n t i b o d y r e s p o n s e a n d i m m u n i t y to RV i n f e c t i o n s
Infection with RV evokes both a local intestinal and a serum antibody response. Intestinal antibodies appear early: RV-specific I g M and I g G may be detected in duodenal secretions in the acute phase of RV GE, persist during convalescence and disappear by 6 - i 2 months. 1~-1sAnti-RV IgA is found in the faeces of infected persons from the fourth day of infection for up to 6 months. 17'18 Faecal anti-RV IgA titres accurately represent the intestinal immune response since they correlate positively with titres in duodenal secretions. 19.20 Serum anti-RV I g M appears early in the acute phase of a primary infection, usually between 5 and 9 days, 16' 17 and disappears within 5 weeks.~l Serum IgA also appears during the first week, peaks at around 2 weeks and persists for at least 4 months. 20 Concentrations of serum and intestinal RV IgA correlate well in infants, children and adults. 19' 22 This may not be the case in neonates who have been found to evoke a mucosal (salivary) IgA response without a concomitant serum antibody response. 2a Beyond the neonatal period, therefore, faecal RV IgA may be useful in assessing immunity to RV infection but only up to about 6 months after infection. Even so, Bernstein et a l . , 24 found that pre-existing faecal antibodies failed to protect against infection. Serum RV I g G titres rise slowly between the first and fourth weeks, are very high 30-45 days after infection, and persist for I 2 - I 5 months. 16' 17.21 Serum neutralising antibodies to RV make their appearance within 2 weeks of infection and are in general specific for the infecting serotype. 25'26 Heterotypic responses to other serotypes, however, have also been reported and such responses appear to depend on the infecting serotype : infection with serotypes I or 2 elicit homotypic responses only, whereas, after infection by serotype 3, neutralising antibodies to serotypes I and 4, as well as to serotype 3, app ear.2~' 27-29 T h e role of antibodies in protecting against RV infection is unclear. Mucosal antibodies certainly do appear to be protective. For example, human milk with an anti-RV IgA concentration >~ I80 g/l, bovine colostrum rich in RV antibodies, and orally administered gamma-globulin containing RVantibodies have all been shown to afford significant passive protection, a°-a2 On the other hand, there was no correlation between pre-existing faecal anti-RV IgA concentrations and protection against infection in adult volunteers.24 It does appear, however, that resistance to clinical disease correlates well with
Rotavirus vaccines in I99o
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homotypic anti-RV secretary IgA concentrations as well as with homotypic neutralising serum antibody titres >~ I28. 25'33 In most vaccine trials to date titres of serum neutralising antibodies have been used as a measure of immunogenicity. 3~-37
R e q u i r e m e n t s for an ideal v a c c i n e
An ideal vaccine should induce substantial, long-lasting immunity against RV diarrhoea in young infants following a single oral dose. It should be administered at 2-3 months of age, since, despite the highest prevalence of the disease in the 6-24 month age group in developed countries, severe rotaviral diarrhoea is found in m u c h younger infants in some third world countries) 8-41 If, as appears probable, multiple doses are required, it would be convenient to combine the vaccine with oral poliomyelitis vaccine, a practice which would ensure greater compliance. Thus, it would be of practical importance to know whether the two vaccines can be given profitably in combination or whether they would interfere with each other as far as immunogenicity is concerned. This question is addressed later in this article. A good vaccine would have to protect against multiple RV serotypes.
A p p r o a c h e s used for r o t a v i r u s v a c c i n e d e v e l o p m e n t
Theoretically, several strategies might be employed for developing vaccines against rotavirus, as follows. (a) H u m a n and animal group A RVs share a common group antigen VP-6 situated in the inner core of the RV particle. 4'42'43 Therefore, cell cultureadapted animal rotavirus could be used as live, attenuated strains in a vaccine. Attenuation implies that the virus is rendered non-pathogenic by multiple passages through cell culture but retains its immunogenic properties. 33 (b) T h e VP-7 outer capsid protein (the major neutralisation antigen) of h u m a n rotavirus (HRV) can be incorporated into an animal RV by coinfecting cell cultures with both a h u m a n and an animal strain. 43'44 T h e resulting 'reassortant' strain might then be used as a vaccine. (c) It is well-known that h u m a n neonatal RV infections are, in the main, asymptomatic or very mild, being partly accounted for by natural attenuation of the ' n u r s e r y ' strains by virtue of a modification in the VP-4 outer capsid protein. 45'46 Thus, natural RV strains from asymptomatic neonates might be used as a vaccine. (d) Multiple passage of h u m a n RV in cell culture results in the production of naturally attenuated strains which may be used as candidate vaccines. 43,47.48 In practice, all four strategies have been tried in attempts to develop candidate live, attenuated oral RV vaccines, with varying results. Virulence in experimental animals is usually gauged by administrating oral HRV (which is normally pathogenic to n o n - i m m u n e newborn calves) to newborn calves which have earlier been ' i m m u n i s e d ' in utero by the candidate vaccine and which have not been fed their mother's colostrum. T h e y are then observed for development of gastro-enteritis. If avirulent by this test, the vaccine is further
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evaluated serially in adult volunteers with anti-RV antibody, in seronegative adults and then in progressively younger persons, first in seropositive and then (if avirulent) in seronegative subjects33 R o t a v i r u s v a c c i n e s u s e d in t r i a l s U s e o f a n i m a l R V s as v a c c i n e s in h u m a n b e i n g s
Experiments in colostrum-deprived piglets showed that cross-protection is afforded by a bovine strain R I T 4237 against h u m a n strains. 49 Two bovine vaccines, the R I T 4237 and the WC 3, as well as the simian strain M M U 18oo6, have been used in field trials in h u m a n beings35' 36.50-5~These are all live attenuated vaccines which have undergone multiple passages in cell culture: I47 passages in the case of R I T 4237 but only I2 in the case of WC 3 and I6 in the case of M M U 18oo6. (a) Bovine R I T 4237 vaccine
Initial placebo-controlled trials of this vaccine, involving more than 3oo infants in Finland, gave a protection rate of over 80 % in 6 - i 2 month oldinfants,35, 36 the response being the same in both those breast-fed and bottlefed. 56 Neutralisation of gastric acidity by administering the vaccine with milk increased the seroconversion rate to 90 % F while protection lasted for at least one epidemic season. However, because of its ineffectiveness in over 400 infants in Africa 58' 59 and in Apache Indians in the U.S.A33--probably due to viral interference--the R I T 4237 has recently been withdrawn by the manufacturers. (b) Bovine W C 3 vaccine This vaccine, derived from a different bovine RV, is used at a five-fold lower concentration and after fewer passages in cell culture than the R I T 4237 vaccine. It gave a neutralising antibody response in 95 % of N o r t h American infants aged 5-I I months. Its efficacy appears to be independent of previous antibody status or antacid treatment of the vaccinees3 ° In a more recent trial involving IO4 infants in Philadelphia, U.S.A., its efficacy was Ioo % against severe (and 76 % against all) RV diarrhoea31 It is currently being evaluated in Israel and the Central African Republic33 T h e mechanism of protection given by the bovine vaccines is unknown. T h e major cross-reactive antigen between bovine and h u m a n RVs is the group-specific inner capsid protein VP-6 which is not involved in the induction of neutralising antibodies.
I8OO6 vaccine Preliminary trials of this vaccine (also known as the RRV-I vaccine) in adults with low antibody titres showed it to be well-tolerated and highly immunogenic, with a seroconversion rate of over 8o%. 5~'6° Significant protection was provided in a small double-blind randomised placebocontrolled field trial in the U.S.A3 ~ In addition, Gothefors et al., 61 showed that it gave Ioo % protection against severe, and 48 % protection against all, RV diarrhoea in a trial involving IO6 infants in Sweden. Flores et al., 54 (c) Rhesus M M U
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performed a similar trial in 247 infants in two low-income communities in Venezuela observed for a period of I year and obtained Ioo % protection against severe RV and 64 % against all RV diarrhoea. In infants between I and 5 months of age the efficacy was 93 %. Studies in Finland and the U.S.A., however, have not confirmed these findings, the protection rate in these varying from o-38 %.53' 62 One explanation for this discrepancy is the fact that, in these later trials, most episodes of diarrhoea were due to serotype r RV, to which the M M U I8OO6 (or RRV-I) is not related by the viral antigen VP-7. By contrast, in the Venezuelan trial, the commonest causative agent was serotype 3 RV which is closely related antigenically to RRV-I by VP-7. T h e seroconversion rate of 8o % found earlier in adults by Kapikian et al., 6° has been confirmed in 5o children aged 3-~z months in T e n n e s s e e ) ~ T h e main adverse reaction encountered with the use of this vaccine in doses of Io 5 or IO6 plaque-forming units (PFU) is fever in 3o-7o% of the vaccinees. T h e Venezuelan study cited above employed a dose of Io 4 P F U but makes no mention of fever or other untoward effects) 4 Reassortant RV vaccines
(a) A bovine-human reassortant vaccine
This vaccine designated WI79-9, the bovine WC 3 rotavirus into which the VP-7 protein from serotype I h u m a n RV has been incorporated, is currently being evaluated in the U.S.A. It is hoped that I o o % protection against diarrhoea caused by the h u m a n serotype I RV is afforded. 53 (b) Rhesus-human reassortant vaccines
Here the VP-7 antigens of h u m a n RVs serotypes I and 2, respectively, have been incorporated into rhesus rotavirus. In Finland 88 % and in the U.S.A. 67 % protection against H R V serotype I diarrhoea has been r e p o r t e d ) 3 (c) Combined rhesus-human reassortant vaccine
A quadrivalent reassortant vaccine combining serotype 3 rhesus rotavirus with h u m a n serotypes I, 2 and 4 has undergone a small field trial in Venezuela. About 75% of 45 recipients showed serum IgA antibody responses; neutralising antibody responses to serotypes I-4 were found in only 4o % of vaccinees. Febrile reactions were reported in 3o % of them but long-term results are as yet unavailable for assessing protection (if any) against diarrhoea. 3v Neonatal human
RV strain vaccines
T h e rotaviral protein VP-4 is altered in the neonatal or ' n u r s e r y ' RV strains, resulting in very mild or asymptomadc natural infections in the corresponding age-group. Babies acquiring such infections when neonates are later partially protected against RV diarrhoea (but not necessarily against RV infection) as shown in a long-term study in Australia. 45 On the basis of this, a naturally attenuated strain of H R V with an altered VP-4 has been developed as a candidate vaccine, named M37, in the U.S.A. ; it cross-reacts with serotypes i and 4 .53 Preliminary results in 22 infants have shown a 50 % serum IgA
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response, a 64 % neutralising antibody response and transient fever in 20 % recipients but information on protection against diarrhoeal illness is so far unavailable. 37 A t t e n u a t e d h u m a n RV v a c c i n e
Limited work on young adult volunteers with a h u m a n strain (the HRV 5 derived from the Wa strain), attenuated by passage in cell culture, gave a seroconversion rate of 6o % without any adverse reactions. 63 Thus, to summarise, of the animal vaccines, one rhesus and two bovine RV vaccines have so far undergone field trials. One bovine vaccine had to be withdrawn due to insufficient efficacy, mainly in third world situations. Efficacy of the rhesus M M U 18006 vaccine has varied in different geographical locations, mainly because of variability in the serotype of the wild virus, the vaccine being most effective against serotype 3 h u m a n rotavirus. T h e single animal RV vaccine which has shown most promising results up to now has been the bovine WC 3 with an efficacy around 9O-lOO %. This seems to have been independent of previous antibody status or antacid treatment of the vaccinees, although field trials larger than those hitherto performed are clearly indicated. A human-bovine reassortant vaccine, WI79-9, appears to show good efficacy but its evaluation is still in the early stages. Rhesus-human reassortant vaccines have shown variable results in early trials. A polyvalent or multiserotype rhesus-human reassortant vaccine, currently under evaluation, may provide the answer as long as inter-serotype interference in antibody response does not take place although, at present, there appears to be an unacceptably high rate of febrile reactions. It is too early to comment on a naturally attenuated h u m a n 'neonatal' RV vaccine. Questions which need to be addressed include the following. (i) Is there a need for fasting before oral vaccination ? (ii) Can a vaccine be given with an ordinary feed ? Most vaccines at present have to be given with a buffered feed. Further work to simplify the procedure is necessary if mass vaccination is to become feasible. (iii) Would anti-RV antibodies or other anti-RV factors in breast milk interfere with the 'take' in breast-fed infants ? (iv) What would be the duration of immunity ? (v) Are multiple doses necessary or would protective concentrations of antibody be sustained in later life by infections with wild strains ? (vi) Could a rotavirus vaccine be administered together with routine oral polio vaccine ? Simultaneous administration of the R I T 4237 vaccine with oral polio vaccine caused a significant reduction both in the number of vaccinees with an anti-RV antibody response (from 74-33 % vaccinees) and in the mean neutralising antibody titre to RV (from 351-193) but the response to the polio vaccine was not affected.64 In another trial, however, infants infected with entero-viruses at the time of receiving the WC3 vaccine failed to show a neutralising antibody response, thereby suggesting viral interference, s° On the other hand, live RV vaccine does not appear to interfere with the response to live oral polio vaccine. 64'65 (vii) Can a single vaccine afford protection against the multiple serotypes, subgroups and electropherotypes of RV ? Since the present answer appears to
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b e n o , this q u e s t i o n r e q u i r e s u r g e n t a t t e n t i o n in t h e l i g h t o f t h e k n o w n c o m p l e x d i v e r s i t y o f r o t a v i r u s e s . 66 (viii) S h o u l d live v a c c i n e s b e u s e d in i m m u n o c o m p r o m i s e d i n f a n t s s u c h as those with human immunodeficiency virus (HIV) infections, Hodgkin's d i s e a s e , l y m p h o m a , l e u k a e m i a , or t h o s e r e c e i v i n g r a d i a t i o n t h e r a p y o r p r o l o n g e d t r e a t m e n t w i t h c o r t i c o - s t e r o i d s ? A t p r e s e n t t h e a n s w e r is no. A l t h o u g h a n t i - R V I g G h a s b e e n d e t e c t e d in t h e s e r u m o f IO i m m u n o d e f i c i e n t children without diarrhoea and who had had prior therapy with gammag l o b u l i n , t h e titres w e r e m u c h l o w e r t h a n t h o s e in h e a l t h y c h i l d r e n . 67 M o r e e x t e n s i v e field trials i n v o l v i n g l a r g e r p o p u l a t i o n s a n d i n c l u d i n g n e o n a t e s n e e d to b e d o n e f o r a t h o r o u g h a n d c o m p r e h e n s i v e e v a l u a t i o n . H a p p i l y , m a n y a r e a l r e a d y u n d e r w a y in v a r i o u s p a r t s o f t h e w o r l d . (I am extremely grateful for the advice, guidance and constructive criticisms of Professor A. Moosa, former H e a d of the D e p a r t m e n t of Paediatrics, and of D r I. Windsor, D e p u t y Director, D e p a r t m e n t of Virology, Faculty of Medicine, University of Natal, D u r b a n . Financial assistance from the South African Medical Research Council is gratefully acknowledged.) References I. Ho M-S, Glass RI, Pinsky PF, Anderson LJ. Rotavirus as a cause of diarrheal morbidity and mortality in the United States. J Infect Dis 1988 : I58 : I 112-1116. 2. Snyder JD, Merson MH. The magnitude of the global problem of acute diarrhoeal disease : a review of active surveillance data. Bull W H O 1982; 6o: 6o5-613. 3. DeZoysa I, Feachem RG. Interventions for the control of diarrhoeal diseases amongyoung children: rotavirus and cholera immunization. Bull W H O 1985; 63:569-583 • 4. Flores J, Nakagomi O, Nakagomi T et al. The role of rotaviruses in pediatric diarrhea. Pediatr Infect Dis J 1986; 5: $53-$62. 5. Kapikian AZ, Cline WL, Greenberg HB et al. Antigenic characteristics of human and animal rotaviruses by immune adherence hemagglutination assay (IAHA): evidence for distinctness of IAHA and neutralization antigens. Infect Immun 1981; 33: 415-425. 6. Thouless ME, Beards GM, Ftewett TH. Serotyping and subgrouping of rotavirus strains by the ELISA test. Arch Virol 1982 ; 73: 219-23o. 7. Flewett TH, Thouless ME, Pilford JN, Bryden AS, Candeias JAN. More serotypes of human rotavirus. Lancet 1978; ii: 632. 8. Hoshino Y, Wyatt RG, Greenberg HB et al. Serotypic similarity and diversity of rotaviruses of mammalian and avian origin as studied by plaque reduction neutralization. J Infect Dis 1984; 149: 694-702. 9- Tursi JM, Albert MJ, Bishop RF. Production and characterization of neutralizing monoclonal antibody to a human rotavirus strain with a human rotavirus strain with a 'super short' RNA pattern. J Clin Microbiol 1987; 25: 2426-2427. IO. Clark HF, Hoshino Y, Bell L M et al. Rotavirus isolate W I 6 I representing a presumptive new human serotype. J Clin Microbiol 1987; 25: 1757-1762. i i. Kalica AR, Garon CF, Wyatt RF et al. Differentiation of human and calf reoviruslike agents associated with diarrhea using polyacrylamide gel electrophoresis of RNA. Virology 1976; 74: 86-92. 12. Beards GM. Polymorphism of genomic RNAs within rotavirus serotypes and subgroups. Arch Virol 1982 ; 74: 65-7o. 13. Rodger SM, Bishop RF, Birch C et al. Molecular epidemiology of human rotaviruses in Melbourne, Australia from 1973 to 1979 as determined by electrophoresis of genome ribonucleic acid. J Clin Microbiol 1981 ; 13: 272-278. 14. Tam JS, Bojian Z, Yongkai Y e t al. Occurrence of rotaviruses in Guangzhou and Hong Kong. J Infect Dis 1988; 157: 357-363.
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