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Appendix D-13
The Prospects for Immunizing Against Rotavirus

DISEASE DESCRIPTION

Rotavirus infection causes an acute diarrheal disease, although both in developed and developing countries there is a greater incidence of asymptomatic infection than there is of disease (Black et al., 1982a; Champsaur et al., 1984). In developing countries, rotavirus diarrhea persists for 10 or more days in 20 percent of patients and often results in moderate to severe dehydration (Black et al., 1982a).

In young infants, the illness generally begins with vomiting, followed by an explosive watery diarrhea and fever. Diarrhea is severe enough to result in isotonic dehydration in 15 to 20 percent of patients (Black et al., 1982a). The stools contain a relatively low concentration of sodium and may be mucoid in about 25 percent of cases, but usually are devoid of blood or pus (Kapikian et al., 1982). Temperature elevations are present in about half of hospitalized patients and generally are low grade. Concurrent clinical signs of pharyngitis, otitis media, or bronchitis may occur in up to one-third of infants; however, recent epidemiological studies suggest that these signs are not specifically associated with rotavirus infection as previously believed (Champsaur et al., 1984).

Mortality may occur in patients with severe dehydration if adequate fluid replacement is delayed. This situation is more frequent in developing countries. Because the risk of significant dehydration is 10 times greater with rotavirus than with other etiologic agents in young infants (Black et al., 1982a), it is probably a major contributor to diarrheal deaths in this age group (Soenarto et al., 1981). Community studies in developing nations also suggest that both symptomatic and asymptomatic infections result in growth retardation, which may have a significant impact on nutritional status (Mata et al., 1983). Surprisingly, however, Black et al. (1984) were unable to demonstrate a relationship between rotavirus infection and growth in Bangladeshi

The committee gratefully acknowledges the advice and assistance of R.E.Black, C.C.J.Carpenter, and H.F.Clark. The committee assumes full responsibility for all judgments and assumptions.



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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Appendix D-13 The Prospects for Immunizing Against Rotavirus DISEASE DESCRIPTION Rotavirus infection causes an acute diarrheal disease, although both in developed and developing countries there is a greater incidence of asymptomatic infection than there is of disease (Black et al., 1982a; Champsaur et al., 1984). In developing countries, rotavirus diarrhea persists for 10 or more days in 20 percent of patients and often results in moderate to severe dehydration (Black et al., 1982a). In young infants, the illness generally begins with vomiting, followed by an explosive watery diarrhea and fever. Diarrhea is severe enough to result in isotonic dehydration in 15 to 20 percent of patients (Black et al., 1982a). The stools contain a relatively low concentration of sodium and may be mucoid in about 25 percent of cases, but usually are devoid of blood or pus (Kapikian et al., 1982). Temperature elevations are present in about half of hospitalized patients and generally are low grade. Concurrent clinical signs of pharyngitis, otitis media, or bronchitis may occur in up to one-third of infants; however, recent epidemiological studies suggest that these signs are not specifically associated with rotavirus infection as previously believed (Champsaur et al., 1984). Mortality may occur in patients with severe dehydration if adequate fluid replacement is delayed. This situation is more frequent in developing countries. Because the risk of significant dehydration is 10 times greater with rotavirus than with other etiologic agents in young infants (Black et al., 1982a), it is probably a major contributor to diarrheal deaths in this age group (Soenarto et al., 1981). Community studies in developing nations also suggest that both symptomatic and asymptomatic infections result in growth retardation, which may have a significant impact on nutritional status (Mata et al., 1983). Surprisingly, however, Black et al. (1984) were unable to demonstrate a relationship between rotavirus infection and growth in Bangladeshi The committee gratefully acknowledges the advice and assistance of R.E.Black, C.C.J.Carpenter, and H.F.Clark. The committee assumes full responsibility for all judgments and assumptions.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries infants. This may be related to the lower incidence of rotavirus infection in this environment relative to E. coli infection. The incidence of rotavirus diarrhea in Bangladesh is estimated to be about 0.5 episodes per child per year (Black et al., 1982a). Neonatal infection is most commonly asymptomatic; the vast majority of neonates with evidence of rotavirus in the stool can be classified as carriers based on both lack of symptoms and the absence of an antibody response (Champsaur et al., 1984). PATHOGEN DESCRIPTION Rotavirus is a double-stranded RNA virus in the Reoviridae family, with a distinctive genome of 11 segments. Serological classification has been somewhat confusing; however, recent work permits separation of distinct serotypes based on outer capsid antigens detected by neutralization with hyperimmune sera (Wyatt et al., 1982). Serotype specificity may, in fact, be determined by two distinct genes, as is the case with influenza virus (i.e., the genes for neuraminidase and hemagglutinin). Four human serogroups have been defined, two of which contain cross-reactive animal rotaviruses, and at least three other serogroups exist containing animal rotaviruses (Hoshino et al., 1984). Epidemiological studies are in progress to determine the prevalence of these serotypes in different parts of the world. The present data indicate that serotypes 1 and 2 are present worldwide. Serotype 3 appears to be less prevalent, and serotype 4 has been found only in Europe (Kapikian, personal communication, 1984). Some heterologous cross-reactivity has been reported between animal and human serotypes 3 and 4 (Hoshino et al., 1984). The number and cross-reactivity of serotypes is obviously important for vaccine development. Rotavirus serotypes may be divided into subgroups based on inner capsid antigens detected by complement fixation, ELISA (enzyme-linked immunosorbent assay), or immune adherence assays (Kapikian et al., 1981). The two well-defined subgroups, 1 and 2, also can be identified by differences in RNA patterns detected by electrophoresis in polyacrylamide-agarose gels (Kalica et al., 1981). Subgroup and serotype antigens are controlled by different segments of the virus genome. In vitro cultivation of human rotaviruses has been difficult in the past. Strain Wa, the prototype serotype 1 rotavirus, was originally propagated in African green monkey kidney cells following 11 passages in newborn, germ-free piglets (Wyatt et al., 1980). Other strains, including DS-1, the serotype 2 prototype strain, were grown following rescue by genetic reassortment with readily cultivated bovine rotaviruses (Greenberg et al., 1981). Recently, many human rotaviruses (up to 75 percent of stool isolates) have been grown successfully in MA-104 cells, a primary embryonic cynomolgus monkey kidney line, following pretreatment of virus by trypsinization and low speed centrifugation (Sato et al., 1981; Urasawa et al., 1981). Protective antigens have not been well defined. There is evidence of cross-protection between animal and human viruses, but the responsible determinants have not been identified (Wyatt et al., 1979).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries HOST IMMUNE RESPONSE Experimental studies in animals have demonstrated that feeding colostrum containing antibody to rotavirus during challenge is protective. The colostrum is not protective if given prior to challenge, however. Epidemiological studies in humans suggest that breast-fed infants are similarly protected, supporting the role of intestinal antibody in the response to rotavirus. Disease due to rotavirus occurs primarily in the 6 to 24 months age group, and by the third year of life essentially all members of populations in developing countries have serologic evidence of prior infection (Black et al., 1982b). Limited data from experimental infections in human adults indicate that homologous protection from clinical manifestations persists for at least 19 months (Kapikian et al., 1983). Both heterotypic and heterosubgroup serologic responses also have been found (Kapikian et al., 1983). Prechallenge serum neutralizing antibody titer is associated with a lower frequency of symptomatic infection and virus shedding following virus challenge. A titer of 1:320 or greater in children less than 2 years of age is indicative of protective immunity and results in a relative risk of 0.3 for rotavirus diarrhea compared to individuals with low titers. The antibody measured may not be directed to the actual protective antigen, however, because titers of 1:320 in the child under 2 are still associated with a relative risk of 6.1 for rotavirus diarrhea compared to older children with similarly high titers (Black et al., 1982b). Although less well documented, an inverse relationship also appears to exist between intestinal antibody level and susceptibility to rotavirus diarrhea. Asymptomatic, naturally acquired, neonatal rotavirus infection has been shown to reduce the severity of subsequent infections, but not to confer immunity against reinfection (Bishop et al., 1983). Recent studies employing a live oral bovine rotavirus vaccine (RIT 4237) indicate that a heterologous antibody response occurs in humans as well (Vesikari et al., 1983). Significant protection in immunized compared to nonimmunized infants was observed during a natural outbreak of rotavirus infection following the immunogenicity and safety trials of this vaccine in Finland (Vesikari et al., 1984). At present no longitudinal data are available to address the question of the duration of protection. However, the period of vulnerability to symptomatic rotavirus infection is largely restricted to the first 2 to 3 years of life, indicating that immunity is acquired and may last for decades, if not for a lifetime. DISTRIBUTION OF DISEASE Geographic Distribution Rotavirus infection has worldwide distribution. The 6 to 24 months age group is the principal target of infection in all regions. In temperate climates, the disease has a distinct seasonality, occurring

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries predominantly in the cold months of the year (Kapikian et al., 1982; Rodriguez et al., 1980). In contrast, in the tropical developing countries, rotavirus infection occurs year-round (Soenarto et al., 1981). Disease Burden Estimates The disease burden estimates for rotavirus, assuming current levels of intervention, are shown in Table D-13.1, and their derivations are discussed in Appendix C. The estimates based on a scenario in which oral rehydration therapy prevents 50 percent of rotavirus deaths are shown in Table D-13.2. PROBABLE VACCINE TARGET POPULATION The principal target for a rotavirus vaccine is the young infant in the first few months of life. Vaccination at this stage should reduce the morbidity and mortality associated with clinical rotavirus infection in the early years. A secondary target might be women of childbearing age. This approach could increase the titer of rotavirus antibody in breast milk to protect nursing infants. The advantage of such passive protection is reduced by the already generally mild or asymptomatic nature of neonatal rotavirus infection and by the small protection afforded by maternal antibody against future symptomatic disease. Rotavirus vaccine appears to be an ideal candidate for inclusion in the World Health Organization Expanded Program on Immunization (WHO-EPI). The target for rotavirus vaccine is precisely the age group currently covered by the EPI program. The immunogenicity of a rotavirus vaccine in this age group remains to be demonstrated, but no special problems are anticipated (in contrast to bacterial polysaccharide vaccines, which may elicit a poor antibody response). In addition, the compatibility of the live virus vaccine with other vaccines given by the oral route must be determined. These are vaccine development problems, and there are no theoretical reasons why they cannot be solved. Vaccine Preventable Illness* Assuming administration of a hypothetically perfect vaccine (conferring long-lasting immunity with one dose) in the first few months of life, the overwhelming majority of the disease burden *   Vaccine preventable illness is defined as that portion of the disease burden that could be prevented by immunization of the entire target population (at the anticipated age of administration) with a hypothetical vaccine that is 100 percent effective (see Chapter 7).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-13.1 Disease Burden: Rotavirus       Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Condition Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity Mild diarrhea 109,979,000 6 5,698,000 4 4,239,000 4 479,000 4 B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work Moderately severe diarrhea 9,776,000 6 46,000 6 34,300 5 20,200 6 C Severe pain, severe short-term impairment, or hospitalization Severe diarrhea 8,729,000 7   7   7   7 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)     n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)     n.a.   n.a.   n.a.   n.a. F Total impairment     n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility     n.a.   n.a.   n.a.   n.a. H Death   873,000 n.a.   n.a.   n.a.   n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-13.2 Disease Burden: Rotavirus, Assuming Increased Use of Oral Rehydration Therapy       Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Condition Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity Mild diarrhea 109,979,000 6 5,698,000 4 4,239,000 4 479,000 4 B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work Moderately severe diarrhea 9,776,000 5.5 46,000 5.5 34,300 5 20,200 5.5 C Severe pain, severe short term impairment, or hospitalization Severe diarrhea 8,729,000 7   7   7   7 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)     n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)     n.a.   n.a.   n.a.   n.a. F Total impairment     n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility     n.a.   n.a.   n.a.   n.a. H Death   436,500 n.a.   n.a.   n.a.   n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries (mostly in children 6 to 24 months of age) could be averted. Hence, 100 percent of the total disease burden is assumed to be vaccine preventable. SUITABILITY AND NEED FOR VACCINE CONTROL Rotavirus is a major cause of diarrheal disease in infants in the developing world and accounts for a disproportionate percentage of dehydration episodes in this population. Because dehydration is a major cause of mortality in developing nations, the need to reduce the incidence of rotavirus disease is evident. The high incidence of this infection in the children of developed nations with excellent standards of hygiene (sanitary feces disposal, clean water supply, and adequate housing) suggests that improvements in the environment of developing nations will not reduce the incidence of the infection. Although breast-feeding has an impact on reducing neonatal infection, the prevalence of rotavirus infection in young infants in the developing world who continue to breast-feed indicates that breast-feeding alone will not be very helpful. Thus, vaccine control should become the major weapon against rotavirus. Alternative Control Measures and Treatments As noted above, alternative measures to control rotavirus are unlikely to succeed. There is no doubt that early use of oral rehydration therapy (ORT) will reduce the incidence of complicating dehydration in rotavirus infection and thus contribute to a reduction in mortality; however, this will not affect the incidence of infection and disease (Sack et al., 1978). Significant and unacceptable morbidity and mortality will continue to occur until a vaccine is available, especially in the areas with inadequate access to medical care. No practicable chemotherapeutic or chemoprophylactic agents are available other than ORT. PROSPECTS FOR VACCINE DEVELOPMENT The protective antigens for rotavirus have not been clearly identified or purified. The one experimental model available to study them is somewhat cumbersome, involving in utero immunization of susceptible animals with candidate vaccines, followed by challenge in the first week of life (Wyatt et al., 1979; Zissis et al., 1983). Experimental human challenge has been accomplished in adults (Kapikian et al., 1983). The most useful studies separate volunteers with high and low titers of preexisting antibody, because it is difficult to find adults without some level of immunity. Safety, immunogenicity, and efficacy trials ultimately will have to be conducted in children and infants. This imposes important ethical and logistical constraints on vaccine development.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Several vaccine types can be developed (Kapikian et al., 1980; National Institute of Allergy and Infectious Diseases, 1985). One approach uses a bovine rotavirus that grows well in tissue culture for induction of protection to cross-related human viruses. The most studied of such candidates is the Nebraska calf diarrhea virus, strain RIT 4237, which already has been tested in adults and young children (Vesikari et al., 1983). (This is designated attenuated high passage bovine rotavirus in Table 5.1.) Although the first few passages of this isolate are not well documented, subsequent passage in primary cell culture is known, and the vaccine appears to be safe, attenuated, and protective in at least 80 to 90 percent of infants 6 to 12 months of age (Vesikari et al., 1985). The bovine virus is from subgroup 1 and appears to provide protection against serotypes 2 and 3 as well (Vesikari et al., 1985). It is not yet clear whether this vaccine will provide adequate protection when administered in the first few months of life, whether it can be administered with oral polio vaccine, and what effect breast-feeding has on protection (Vesikari et al., 1985). Another group of candidate rotavirus vaccines derived from bovine strains are also in development. These differ from RIT 4237 in strain origin, mode of passage, manner of propagation, as well as total cell passage level (Clark, personal communication, 1985). Collectively, these candidates are designated attenuated low passage bovine rotavirus in Table 5.1. The third rotavirus vaccine candidate for which predictions are made in Table 5.1 is based on a rhesus monkey rotavirus isolate (RRV). This was passaged nine times in primary monkey kidney cell culture and seven times in FRhL-2 cell culture, a rhesus monkey lung diploid cell strain developed by the Food and Drug Administration as a potential substrate for vaccine production. Eighty-four percent of adult volunteers developed a neutralizing antibody response to RRV after oral administration of it. Studies in children are in progress (Kapikian et al., 1985; National Institute of Allergy and Infectious Diseases, 1985). Human rotavirus grown in cell culture is another possible vaccine candidate (Kapikian et al., 1985). Techniques using trypsin-treated virus grown in MA 104 cells or reassortment virus obtained by co-cultivation with bovine rotavirus presumably will permit culture of all major serotypes and subgroups of clinical importance. Attenuation may be achieved by a variety of methods, such as prolonged passage, temperature mutations, reassortment, or direct mutagenesis. Virulence of these strains can be studied in animal models (gnotobiotic newborn piglets) or in human adult volunteers with absent or low-titer serum antibody; however, work of this type is laborious and slow. Another potential vaccine type would involve the use of recombinant DNA techniques to clone rotavirus genes for insertion into plasmid vectors. Production of rotavirus antigens in vitro could be used as a source of purified antigen vaccines. This work is in its infancy and will require considerably more basic research before it reaches fruition; therefore, predictions for this vaccine are not included in Chapter 5.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries An additional vaccine type would be a synthetic peptide vaccine consisting of the peptide portions of key protective protein or glycoprotein antigens. These must be identified and synthesized before their protective efficacy can be demonstrated. It is uncertain how large these molecules will be or how difficult they will be to synthesize in quantity. Depending on size, they may or may not be immunogenic without inclusion of suitable adjuvants or coupling to carriers. Although some work is now being done in this area, the synthetic peptide approach probably will be the slowest to yield a useful product. Again, predictions for this vaccine are not included in Chapter 5. Because the target population will be young infants, on whom controlled challenge studies cannot be performed, field studies will need to be designed to take advantage of the natural disease occurrence of rotavirus infection following immunization. This will necessitate a large population in a highly endemic region and prolonged follow-up. Such trials will require extensive field epidemiology and laboratory backup and undoubtedly will be expensive. Major points at which the National Institutes of Health could have significant leverage include characterization of the virulence factors and relevant protective antigens, production and testing of human cultivated rotavirus vaccine strains in experimental animals and human volunteers, and field tests of ready vaccines. This work could be incorporated into both the intramural and the extramural research programs of the National Institute of Allergy and Infectious Diseases. REFERENCES Bishop, R.F., G.L.Barnes, E.Cipriani, and J.S.Lund. 1983. Clinical immunity after neonatal rotavirus infection. A prospective longitudinal study in young children. New Engl. J. Med. 309(2):72–76. Black, R.E., K.H.Brown, S.Becker, A.R.M.Abdul Alim, and I.Huq. 1982a. Longitudinal studies of infectious diseases and physical growth of children in rural Bangladesh. II. Incidence of diarrhea and association with known pathogens. Am. J.Epidemiol. 115:315–324. Black, R.E., H.B.Greenberg, A.Z.Kapikian, K.H.Brown, and S.Becker. 1982b. Acquisition of antibody to Norwalk virus and rotavirus and relation to diarrhea in a longitudinal study of young children in rural Bangladesh. J. Infect. Dis. 145:483–489. Black, R.E., K.H.Brown, and S.Becker. 1984. Effects of diarrhea associated with specific enteropathogens on the growth of children in rural Bangladesh. Pediatrics 73:799–805. Champsaur, H., M.Henry-Amar, D.Goldszmidt, J.Prevot, M.Bourjouane, E.Questiaux, and C.Bach. 1984. Rotavirus carriage, asymptomatic infection, and disease in the first two years of life. II. Serologic response. J. Infect. Dis. 149:675–682. Clark, H.F. 1985. Personal communication, Children’s Hospital of Philadelphia, Penn.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Greenberg, H.B., A.R.Kalica, R.G.Wyatt, R.W.Jones, A.Z.Kapikian, and R.M.Chanock. 1981. Rescue of noncultivable human rotavirus by gene reassortment during mixed infection with ts mutants of cultivable bovine rotavirus. Proc. Natl. Acad. Sci. USA 78:420–424. Hoshino, Y., R.G.Wyatt, H.B.Greenberg, J.Flores, and A.Z.Kapikian. 1984. Serotypic similarity and diversity of rotaviruses of mammalian and avian origin as studied by plaque-reduction neutralization. J. Infect. Dis. 149:694–792. Kalica, A.R., H.B.Greenberg, R.T.Espejo, J.Flores, R.G.Wyatt, A.Z. Kapikian, and R.M.Chanock. 1981. Distinctive ribonucleic acid patterns of human rotavirus subgroups 1 and 2. Infect. Immun. 33(3):958–961. Kapikian, A.Z. 1984. Personal communication, National Institutes of Health, Bethesda, Md. Kapikian, A.Z., R.G.Wyatt, H.B.Greenberg, A.R.Kalica, H.W.Kim, C.D.Brandt, W.J.Rodriguez, R.H.Parrott, and R.M.Chanock. 1980. Approaches to immunization of infants and young children against gastroenteritis due to rotaviruses. Rev. Infect. Dis. 2(3):459–469. Kapikian, A.Z., W.L.Cline, H.B.Greenberg, R.G.Wyatt, A.R.Kalica, C.E.Banks, H.D.James, Jr., J.Flores, and R.M.Chanock. 1981. Antigenic characterization of human and animal rotaviruses by immune adherence hemagglutination assay (IAHA): Evidence for distinctness of IAHA and neutralization antigens. Infect. Immun. 33(2):415–425. Kapikian, A.Z., H.B.Greenberg, R.G.Wyatt, A.R.Kalica, H.W.Kim, C.D.Brandt, W.J.Rodriguez, R.H.Parrott, and R.M.Chanock. 1982. Viral gastroenteritis. Pp. 283–326 in Viral Infections of Humans: Epidemiology and Control, 2d ed., A.S.Evans, ed. New York: Plenum. Kapikian, A.Z., R.G.Wyatt, M.M.Levine, R.H.Yolken, O.H.VanKirk, R.Dolin, H.B.Greenberg, and R.M.Chanock. 1983. Oral administration of human rotavirus to volunteers: Induction of illness and correlates of resistence. J. Infect. Dis. 147(1):95–106. Kapikian, A.Z., K.Midthun, Y.Hoshino, J.Flores, R.G.Wyatt, R.I. Glass, J.Askaa, O.Nakagomi, T.Nakagomi, R.M.Chanock, M.M. Levine, M.L.Clements, R.Dolin, P.F.Wright, R.B.Belshe, E.L. Anderson, and L.Potash. 1985. Rhesus rotavirus: A candidate vaccine for prevention of human rotavirus disease. Pp. 357–367 in Vaccines 85. Molecular and Chemical Basis of Resistance to Parasitic, Bacterial, and Viral Diseases, R.A.Lerner, R.M. Chanock, and F.Brown, eds. Cold Spring Harbor, N.Y.: Cold Spring Habor Laboratories. Mata, L., A.Simhon, J.J.Urrutia, R.A.Kronmal, R.Fernandez, and B.Garcia. 1983. Epidemiology of rotavirus in a cohort of 45 Guatemalan Mayan Indian children observed from birth to the age of three years. J. Infect. Dis. 148(3):452–461. National Institute of Allergy and Infectious Diseases. 1985. Program of Accelerated Development of New Vaccines. Progress Report. Bethesda, Md.: National Institutes of Health.

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