Llama Antibody, Rotavirus Diarrhoea, Children
Condition: Male Children; 6-24 Months Old With Rotaviral Diarrhoea; Non-cholera Patients
MeSH terms: Diarrhea
Study type: Interventional
Phase: Phase 2

Summary: 
      The investigators hypothesize that :

      oral administration of VHH batch 203027 will be

        -  safe and tolerable for healthy Bangladeshi humans of all age groups (Part I)

        -  effective in reducing severity of diarrhoea in children with proven rotavirus infection
           (Part II). This entry only covers Part II.
    

Detailed description: 
      Brief Summary Study investigating the efficacy of oral administration of VHH antibody
      fragment derived from antibodies as found in milk of llamas and camels via a prototype food
      product in reducing the severity of rotavirus diarrhoea in children.

      Detailed Description

      Introduction Rotavirus is the leading viral enteropathogen, which is responsible for 11-71%
      of all diarrhoea episodes in infants and children worldwide. In developing countries,
      rotavirus is associated with more than 125 million episodes of diarrhoea each year (Cook et
      al. 1990), leading to an estimated 600,000 deaths. It is responsible for 60% of all
      diarrhoeal episodes, 20-60% of diarrhoeal hospitalizations, and 20% of diarrhoea-related
      deaths in children <5 years of age (Perez-Schael et al. 1997). In the United States of
      America alone, rotavirus is associated with 3% of all hospitalizations of children younger
      than 5 years with medical and indirect costs of over US$ 1 billion each year (Glass et al.
      1991). In many localities deaths from rotavirus infections persist despite national programs
      to encourage the use of oral rehydration therapy.

      Current management of rotavirus gastroenteritis Current management of rotavirus diarrhoea
      includes prevention of dehydration, or management of dehydration using oral or intravenous
      rehydration, as appropriate, and continued feeding. Early resumption of normal feeding is
      encouraged to enhance mucosal repair and to minimize nutritional consequences of infection.
      The children of developing countries might benefit from zinc supplementation, but its mode of
      delivery and cost effectiveness are yet to be decided in rotavirus diarrhoea. No specific
      treatment is currently available to reduce the duration or severity of this illness.
      Therefore, rotavirus-induced diarrhoea, which is considered to be a self-limited disease, is
      responsible for significant childhood deaths in the developing countries (Glass et al. 1996).

      Active immunization against rotavirus infection The development, testing and eventual use of
      an effective, safe and inexpensive rotavirus vaccine would be the most efficient method for
      preventing severe disease and deaths in developing countries. Rapid progress has been made,
      and several candidate rotavirus vaccines have been developed and tested. Two rotavirus
      vaccines, Rotarix (GlaxoSmithKline Biologicals, Belgium) and RotaTeq (Merck & Co., USA) have
      recently entered the market in the developed world. Both vaccines appear to be safe with
      respect to intussusception, and are highly efficacious in preventing severe gastroenteritis
      due to rotavirus strains carrying predominantly serotype G1 (Cunliffe & Nakagomi 2005).
      Confirmation of the safety and efficacy of both vaccines in developing countries is still
      needed. Moreover, assessment of the ability of each vaccine to provide protection against
      increasingly diverse population of rotavirus strains will depend on continuous surveillance
      on the strain and development of newer vaccines as newer serotypes predominate in different
      geographical locations, which may not be easy for the developing countries. There thus is a
      clear need to define improved, cost effective interventions in the management of rotavirus
      diarrhoea until the time an effective, safe and inexpensive vaccine, affordable to the
      developing countries, is available.

      Passive immunisation for rotavirus-induced diarrhoea; There are good reasons to hypothesize
      that passive immunisation could be useful in the management of human rotavirus diarrhoea. For
      example, oral administration of rotavirus-neutralizing antibodies has been found to modulate
      the rotavirus-induced diarrhoea in children. Beneficial prophylactic (Barnes et al. 1982) and
      therapeutic effects (Guarino et al. 1991), in terms of reduction of duration and severity of
      rotavirus diarrhoea, have also been observed in association with orally administered human
      IgG preparations. The use of human antibody preparation, however, is limited due to the risk
      of viral contamination and high production and supply chain costs of such product(s) and very
      low bio-availability.

      An alternative source of antibodies, safe and easy to produce, was later developed in hyper
      immunized bovine colostrums by vaccinating pregnant cows against human strains of rotavirus.
      This approach has also been effectively used for prophylactic (Davidsson et al. 1989) and
      therapeutic benefits (Mitra et al. 1995, Sarker et al. 1998) in rotavirus diarrhoea in
      hospitalized children. In a recently concluded study in children with rotavirus diarrhoea in
      Bangladesh, we have observed a modest benefit from oral administration of immunoglobulin
      extracted from eggs of chicken immunized with human strains of rotavirus (Sarker et al.
      2001).

      Passive immunization for prevention or treatment of enteric infections generally requires
      relatively large amounts of antibody, particularly at the mucosal sites where antibodies are
      rapidly cleared. Therefore, these modalities, although proven to be effective, become
      expensive due to requirement of larger doses of antibodies. The other limitations of the
      conventional IgG antibodies include their poor stability and complex nature that limits their
      large-scale production. A promising solution for these problems in large-scale antibody
      production came, rather unexpectedly, from the nature itself- camels and llama posses an
      unusual type of IgG antibodies (IgG2 and IgG3) that are devoid of light chains- the "heavy
      chain" antibodies.

      Selection of heavy chain antibody fragments In llama and camel, the "heavy chain" IgG
      antibodies co-exist with the "conventional" IgG (IgG1) (Hamers-Casterman et al. 1993). In
      contrast to conventional antibodies, the heavy chain antibodies are devoid of the light
      chains. Therefore, the binding domain of the heavy chain antibodies consists only of the
      variable domain of the heavy chain (VHH) in contrast to the binding domain of the
      conventional antibodies which consists of a variable domain of the heavy chain (VH) and one
      of the light chain (VL). The biochemical properties of llama VHH antibody fragments are
      superior to the Fv fragments (VH + VL) of conventional IgG antibodies. Although the VHH
      antibody fragments have a simple antigen binding structure with only one domain, it possesses
      high affinity, and is extremely thermostable (van der Linden et al., 1999). Furthermore, they
      are well expressed and secreted by the bakers yeast Saccharomyces cerevisiae, allowing for a
      large-scale cost effective production (Frenken et al., 2000). This process will make the VHH
      fragments an affordable ingredient for food products and will widen their availability to the
      general population of developing countries.

      VHH as a potential food ingredient Many people in African/Arabic countries regularly consume
      camel milk. In 1992, it was observed that camel milk contains high titres of antibodies
      against rotavirus (el Agamy et al 1992).The antibody fragment in VHH batch 203027 is a
      fragment of those antibodies assumed to be present in camel/llama milk. Thus, the
      investigational product can be classified as a food ingredient As from its start in 1999, the
      aim of Unilever's "VHH" project was to develop an affordable food for developing countries,
      which "may help in reducing the risk for rotavirus infections". This type of claim fits very
      well into the definitions put forward by the European Union-sponsored Concerted Action on
      Functional Foods Science in Europe (FUFOSE) (Diplock et al 1999). The FUFOSE terminology's
      for 'enhanced function' (type A) and 'reduction of risk of disease' (type B) claims are now
      widely adapted by many national and international codes of practice, including Codex
      Alimentarius. It was especially developed in the 1990's to allow the delineation between
      functional foods from drugs. In this context, we would also like to refer to the EC
      Regulation No 258/97 of the European Parliament and of the Council of 27 January 1997
      concerning novel foods and novel food ingredients and the EU regulation 1924/2006 on
      nutrition and health claims made for foods. The efficacy of VHH fragments in reducing the
      risk for developing rotavirus diarrhoea when supplied in a food format will be tested in an
      additional trial Safety of application of VHH antibody fragment Safety of oral application of
      VHH antibody fragment has been proven in two studies executed in the Netherlands and
      Bangladesh, including adult and children above the age of 6 months.

      Comparison:

      We will compare with the effect of VHH antibody fragment against placebo in children with
      proven rotavirus diarrhoea hospitalized at the ICDDR,B. This intervention will be on top of
      the standard treatment, including oral rehydration treatment.
    

Intervention name(s): VHH batch 203027; Placebo product
Intervention type(s): Drug; Drug
Intervention description(s): The active product is 165 mg of VHH batch 203027 and 835 mg maltodextrin with 0.5% (w/w) caramel colour in 10 mL ORS. The osmolality (concentration of the osmotically active substances in the solution such as sugar molecules, salts etc. ) of this solution will be around 60 mOsmol/kg. The mixture of the 165 mg of VHH batch 203027 and 835 mg maltodextrin (0.5% (w/w) caramel colour will be provided per sachet.; The Placebo treatment consisted of 1000 mg of maltodextrine with 5% (w/w) caramel colour in 10 mL ORS.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: llama antibody; rotavirus diarrhoea; children