Treatment

For the cornerstone of treatment of acute diarrhea, i.e. the restoration of fluid and electrolyte homeostasis95,96 see Chapter 39.

For children hospitalized with severe rotavirus diarrhea, passive immune treatment should be considered. Several studies have shown that oral administration of human serum immunoglobulin is associated with an effective antiviral effect. Human immunoglobulin, including pooled gammaglobulin, bovine colostrums, or human milk, may decrease the frequency and duration of diarrhea.97 Human immunoglobulin was initially used to treat children with life-threatening rotavirus diarrhea.98 In a double-blind, placebo-controlled study oral administration of human serum immunoglobulin, in a single bolus of 300 mg/kg body weight, resulted in faster recovery and early discharge of immunocompetent children admitted to hospital with severe rotavirus diarrhea, without adverse effects99 (Figure 9.5). The same treatment was given to children with AIDS and severe rotavirus infection, and led to rapid remission of diarrhea and permanent clearance of the virus.100 We currently give human immuno-globulin to children hospitalized with severe rotavirus infection and to patients at risk of a poor outcome.101

Human immunoglobulin, although expensive, is widely available. Its efficacy might be related to high titers of specific neutralizing antibodies to rotavirus. Specific titers are consistently detected in preparations commercially available for intravenous use, because of the high frequency of rotavirus infection and the consequent widespread immune response. The efficacy of immunoglobu-lin is probably related to dose- and time-related direct neutralization of rotavirus, which prevents enterocyte infection and cell death.18 Preliminary experimental evidence indicates that immunoglob-ulin prevents both the cytotoxic and the entero-toxic effect induced by rotavirus in human entero-cytes.102 Thus, immunoglobulin should be administered orally early in the course of the disease for maximum efficacy.

This information may be of practical relevance, while awaiting the development of safer vaccines that will hopefully be effective, for normal or compromised immune function.

Vaccine development Rotavirus

A review of the global prevalence of rotavirus disease was published in 1985, showing that rotavirus accounted for 6% of diarrhea episodes and 20% of deaths caused by diarrhea in children less than 5 years of age in developing countries.103 The incidence of rotavirus disease was similar in both industrialized and developing countries, suggesting that adequate control may not be achieved by improvements in water supply,

Days

Figure 9.5 Stool frequency (stools/24 h) in children hospitalized because of Rotavirus treated with human serum immunoglobulin administered per oral route in a single dose of 300 mg/kg body weight (•) and control children (o). Values are means ± SEM. *p <0.05 (from reference 118).

hygiene and sanitation. Based on the results of a recent paper, rotavirus is still a major threat to child health worldwide.40

After more than 15 years of basic research and clinical trials, a live-attenuated rhesus rotavirus-tetravalent vaccine (RRV-TV), was licensed by the Food and Drug Administration. However, the lifespan of the RRV-TV was short. After initial marketing and after nearly 1.5 million doses already administered in 9 months, the Centers for Disease Control withdrew the vaccine recommendation because of the possible association of the vaccine with intestinal intussusception, and the RRV-TV was removed from the market.104 This event represented a major drawback and introduced new complications in producing a safe and effective vaccine for children, particularly in the developing world, where the vaccine is mostly needed to reduce high mortality rates.

Recent epidemiological surveillance of circulating rotavirus strains, performed to follow the impact of the RRV-TV vaccine, raised questions about whether the RRV-TV would be effective in all settings. Rotavirus strains are characterized into glycoprotein (G) serotypes based on the antigenic properties of their VP7 surface protein. The reassortant RRV-TV vaccine contained G serotypes 1 to 4. In developed countries, more than 80% of rotavirus strains circulating in humans belongs to G serotypes 1 to 4. In the developing world, unusual rotaviruses (G5, G8, G9, or G10) are detected with increasing prevalence. The detection of unusual G9 strains in several developed countries indicates the appearance of more G serotypes in the developed world as well. Thus, vaccine formulations may need to be modified to encompass the diversity of rotavirus strains in particular geographic regions.

Development of alternative vaccination strategies, e.g. virus-like particles (VLPs), vector-expressed proteins, and DNA immunization, continues to be pursued. Among these, preclinical data are strongest for VLPs, because these non-replicating particles are immunogenic and are able to induce protective immunity in several animal models. A number of other candidate rotavirus vaccines have been developed. A summary of vaccines currently in human trials is given in Table 9.7.105 The development of new vaccines is complicated by a lack of understanding of which proteins are essential to prevent diarrhea in children. Thus, even

Table 9.7 Live, attenuated, oral rotavirus vaccines currently in reference 105)

human trials (modified from

Product

Company

Concept

LLR

Lanzhou Institute of Biological Products (China)

monovalent lamb strain (P[12]G10)

Rotateq

Merck (USA)

WC-3 based multivalent human-bovine reassortant

Rotarix (89-12)

GlaxoSmithKline (Belgium)

monovalent human strain (P[8]G1)

UK-reassortant vaccine

Wyeth Ayerst/NIH (USA)

UK-based multivalent human-bovine reassortant

RV3

University of Melbourne (Australia)

neonatal strain (P[6]G3)

116E

Bharat Biotech (India)

neonatal strain (P[11]G9)

I321

Bharat Biotech (India)

neonatal strain (P[11]G10)

though a rotavirus vaccine was licensed, correlates of protective immunity remain relatively unclear.

'Norwalk-like viruses'

Some human study volunteers never become infected after challenge with NLV, perhaps reflecting the recent finding that NLVs recognize human histoblood group antigens as receptors, defining host susceptibility. Immunity to NLV infections is believed to be short lived, as volunteers were re-infected with the same strain within months of previous challenge.

Self-assembled recombinant capsid proteins of Norwalk virus (rNV) into VLPs have been tested as oral immunogens.106 Preclinical studies in mice and phase I studies in healthy adult volunteers have shown that these VLPs are immunogenic in the absence of adjuvant, and high doses (250 mg) delivered orally were safe and elicited antibody responses in all volunteers. The positive results obtained with oral delivery of rNV VLPs have stimulated new vaccine developments, including the expression of rNV in tobacco and potato tubers.107 RNV VLPs expressed in potato tubers were also immunogenic when given to volunteers orally.108 The protective efficacy of these candidate vaccines in human volunteers is currently under study.

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