Safety, Reactogenicity and Immunogenicity of Heat-stable Rotavirus Vaccine (HSRV) in Adults and Infants
Condition: Rotavirus Gastroenteritis
MeSH terms: Gastroenteritis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Rotaviruses are the leading cause of severe, dehydrating diarrhoea and related deaths in
      children aged less than 5 years worldwide and are reported to infect nearly every child by
      the age of 5 years. About 90% of all rotavirus-associated fatalities occur in low income
      countries in Africa and Asia and are related to poor health care. In view of high global RVGE
      burden, the World Health Organization (WHO) on 5th June 2009, recommended the inclusion of
      rotavirus vaccine in all the national immunization programs.

      Currently available rotavirus vaccines, RotaTeq® and Rotarix®, are WHO prequalified vaccines
      which are stable for recommended duration at storage temperature between 2-8 °C. However, if
      these vaccine are exposed to temperatures above 30 °C, the vaccine has to be discarded due to
      lost potency. It is very difficult to maintain the cold chain required to conserve the
      vaccine potency particularly in developing and low income countries, resulting in large
      amount of vaccine being wasted and in worst case scenario, endangering the lives of potential
      recipients. The WHO estimates that nearly half of freeze-dried and quarter of liquid vaccines
      are wasted each year. One of the biggest contributors to this wastage is disruption of the
      cold chain systems.

      Hilleman Labs new Rotavirus vaccine is a lyophilized heat stable rotavirus vaccine comprising
      of five live attenuated reassortant rotaviruses similar to RotaTeq®. The new heat stable
      rotavirus vaccine (HSRV) formulation offers a stability profile of 9 months at 45 °C and 12
      months at 37 °C. This new heat stable formulation (HSRV) could be transported in
      non-refrigerated supply chain significantly reducing the cost and complications associated
      with transporting vaccine to remote corners of the developing world. Heat-stable rotavirus
      vaccine (HSRV) has a potential to sustain high temperatures frequently encountered in regions
      where majority of rotavirus burden exists and has potential to partially or completely
      eliminate cold chain dependence.

      The current study has been designed to test for the first time in humans, the safety and
      tolerability of the new heat stable rotavirus vaccine (HSRV) in adults; followed by safety
      and immunogenicity in infants of age 6-8 weeks, as compared to the licensed RotaTeq® vaccine.
    

Detailed description: 
      Rotaviruses are the leading cause of severe, dehydrating diarrhea and related deaths in
      children aged less than 5 years worldwide and are reported to infect nearly every child by
      the age of 5 years. About 90% of all rotavirus-associated fatalities occur in low income
      countries in Africa and Asia and are related to poor health care. In most low income
      countries in Asia and Africa, rotavirus epidemiology is characterized by one or more periods
      of relatively intense rotavirus circulation against a background of year-round transmission,
      whereas in high income countries with temperate climates a distinct winter seasonality is
      typically observed. In 2008, WHO estimated approximately 453,000 (420,000-494,000) rotavirus
      gastroenteritis (RVGE) associated child deaths worldwide. These fatalities accounted for
      about 5% of all child deaths with a cause-specific mortality rate of 86 deaths per 100,000
      population aged less than 5 years. In view of high global RVGE burden, the World Health
      Organization (WHO) on 5th June 2009, recommended the inclusion of rotavirus vaccine in all
      the national immunization programs.

      As in other Asian countries, Rotavirus infection is a significant cause of illness and
      hospitalizations in Bangladesh with approximately 2.4 million cases being reported every year
      and nearly two-thirds of all diarrhea-related hospitalizations in children under age 5. While
      progress has been made in reducing diarrhea-related deaths among children, it is still one of
      the leading causes of illness among children under 5 in Bangladesh. About half of all
      rotavirus hospitalizations were among infants age 6-11 months, Rotavirus vaccines could have
      a powerful public health impact if introduced into Bangladesh's national immunization
      program.

      The basis for developing a rotavirus vaccine rested on the observation that wild-type
      rotavirus infection immunized children against subsequent disease. The immunity from
      wild-type infection does not prevent all subsequent infections; however, it provides nearly
      complete protection against severe disease and substantial protection against mild disease.
      The five most prevalent rotavirus genotype/serotype combinations are G1P1A[8], G2P1B[4],
      G3P1A[8], G4P1A[8], and G9P1A[8].

      Currently, RotaTeq® and Rotarix® are the two WHO prequalified vaccines which are stable for
      recommended duration at storage temperature between 2-8 °C. Studies indicate that if these
      currently available vaccine, for example RotaTeq®, is inadvertently exposed or stored at
      temperatures above 8 °C, the potency is maintained for the maximum exposure of 48 hours at 9
      °C to 25 °C or for a bare 12 hours at 26 °C to 30 °C. However, if RotaTeq® vaccine is exposed
      to temperatures above 30 °C, the vaccine has to be discarded due to lost potency. There is
      limited data to suggest that if the vaccine is inadvertently exposed to temperatures below 0
      °C, the potency of the vaccine is maintained. Another, currently available freeze dried
      vaccine i.e. Rotarix® vaccine exhibits stability with a shelf life of 36 months at 2 °C to 8
      °C.

      Hence these vaccines do not possess enough thermostability profile suitable for storage
      outside cold chain for any meaningful amount of time and needs to be stored and transported
      under refrigeration. It is very difficult to maintain the cold chain required to conserve the
      vaccine potency particularly in developing and low income countries, resulting in large
      amount of vaccine being wasted and in worst case scenario, not providing protection against
      rotavirus infection to potential recipients. Many other existing vaccines do exhibit some
      degree of thermostability, however, the existing licensed vaccines possess shorter period of
      thermostability (e.g. VVM 7 or VVM 14) which fails to address the issues in developing
      countries especially in region of extreme climatic conditions, reaching up to 40 °C.

      Heat Stable Rotavirus Vaccine is a lyophilized heat stable rotavirus vaccine comprising of
      five live reassortant rotaviruses in RotaTeq®. The parent strains of the reassortants were
      isolated from human and bovine hosts. Four reassortant rotaviruses express one of the outer
      capsid proteins (G1, G2, G3, or G4) from the human rotavirus parent strain and the attachment
      protein (P7) from the bovine rotavirus parent strain. The fifth reassortant virus expresses
      the attachment protein, P1A (genotype P[8]), referred to as P1[8], from the human rotavirus
      parent strain and the outer capsid protein G6 from the bovine rotavirus parent strain. These
      reassortants were suspended in stabilizer solution which was then lyophilized to obtain
      thermostable cake. This lyophilized cake will be reconstituted using a reconstitution buffer.
      There are no preservatives or thimerosal present in the vaccine. The new heat stable
      rotavirus vaccine (HSRV) formulation offers higher titer value even at extreme temperature
      conditions up to 45 °C for prolonged periods of time. This new heat stable formulation (HSRV)
      could be transported in non-refrigerated supply chain significantly reducing the cost and
      complications associated with transporting vaccine to remote corners of the developing world.
      The bulk of reassortants virus have been procured directly from Merck and Co., USA, currently
      licensed in USA and many countries as liquid formulation RotaTeq®, offering an easier
      regulatory path for new heat-stable rotavirus vaccine licensure & WHO prequalification.
      Heat-stable rotavirus vaccine (HSRV) has a potential to sustain high temperatures frequently
      encountered in regions where majority of rotavirus burden exists and has potential to
      partially or completely eliminate cold chain dependence.

      The aim of the current study is to assess the safety and reactogenicity of a single dose of
      Hilleman Labs.' oral live attenuated HSRV vaccine in healthy adults aged 18 years to 45 years
      followed by safety & immunogenicity evaluation in infant population 6-8 weeks of age. In
      current study, adult subjects will either receive a single dose of oral live attenuated HSRV
      vaccine or placebo at Day 0. There will be a safety follow-up for all subjects for a period
      of 14 days after vaccination. The investigators intend to establish the safety of HSRV in
      healthy adults prior to testing in infant population. Acceptable safety data from the adult
      cohort will allow enrolment of subjects in the infant cohort, after approval from study DSMB.
    

Intervention name(s): Heat Stable Rotavirus (HSRV) Vaccine; Placebo for Heatstable Rotavirus vaccine; RotaTeq®
Intervention type(s): Biological; Biological; Biological
Intervention description(s): It is a lyophilized live attenuated pentavalent (G1-G4 and P1[8]) heat-stable rotavirus vaccine (HSRV) comprising of all the five rotavirus strains as in licensed RotaTeq® vaccine for protection against rotavirus infection; It is a lyophilized formulation comprising of all the inactive ingredients as in heat stable rotavirus vaccine without any rotavirus; It is a pentavalent human-bovine (WC3) reassortant live-attenuated, oral vaccine developed by Merck Research Co., West Point, Pennsylvania, USA. This vaccine contains five live reassortant rotaviruses. Four reassortant rotaviruses express the VP7 protein (G1, G2, G3, or G4) from the human rotavirus parent strain and the attachment protein (P7[5]) from bovine rotavirus parent strain WC3. The fifth reassortant virus expresses the attachment protein (P1A[8]) from the human rotavirus parent strain and the outer capsid protein G6 from the bovine rotavirus parent strain.
Other intervention name(s): HSRV; Placebo; Active Comparator
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Prevention