Study of a Live rNDV Based Vaccine Against COVID-19
Condition: SARS-CoV-2 Infection
MeSH terms: COVID-19
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a Phase 1, open-label, non-randomized, dose-escalation study using three doses and
      two schemes of administration of a recombinant vaccine against SARS-CoV-2 based on a viral
      vector (Newcastle Disease virus) in 90 healthy volunteers at a single research site in Mexico
      City.
    

Detailed description: 
      The lack of highly effective treatments against COVID-19 and the social and economic impact
      that the current pandemic has exerted on public health highlights the uncontested importance
      of developing vaccines that, in addition to their safety and ability to induce a protective
      response, are logistically suitable for massive administration across a variety of countries
      and settings.

      This is the first clinical study of the development program of a vaccine based on a unique
      recombinant viral vector technology that has been successful in the design of avian vaccines
      and that has no contraindication for use in humans.

      The recombinant vaccine subject to research in this study is based on an active viral vector
      of a recombinant Newcastle Disease virus (rNDV) LaSota strain, in which the gene that codes
      for the S glycoprotein of SARS-CoV-2 has been inserted.

      The Newcastle Disease Virus (NDV) is a paramyxovirus responsible for the Newcastle Disease in
      birds. There are three main families of NDV according to the level of virulence. The one with
      the lowest virulence is the lentogenic group. One lentogenic viral strain is LaSota (NDV_LS),
      which is broadly used in the development of avian vaccines. The LaSota strain seems to
      replicate only at the site of inoculation and, although it does not reach the lymph nodes, it
      reduces the induction of pro-inflammatory cytokines while boosting a robust protective immune
      response. Very importantly, this virus cannot insert itself into the human genome.

      One of the key factors for an increased virulence in NDV is the activation of the cleavage
      site that corresponds to the protein F precursor phenotype. In highly virulent strains, the
      cleavage is performed by ubiquitous intracellular proteins, which leads to a widespread
      replication in birds.

      However, the cleavage site in attenuated or non-virulent strains is activated by a secretory
      protease which restrains viral replication to mucosal surfaces. This is the same secretory
      protease which acts in NDV-LS in humans and non-human primates, limiting viral replication to
      the upper airways.

      It is of note that the NDV genome is non-segmented. For this reason, transcription results in
      a single-stranded RNA which provides the genome with enough stability to avoid reassortment
      events. These features underpin the antigenic and genetic stability that have contributed to
      the success of NDV across decades as a vaccine vector.

      The recombinant nature of the viral vector is based in the design and synthesis of a gene
      that codes for the spike protein in SARS-CoV-2. Such design is based in the sequence of the
      Wuhan-Hu-1 virus (NC_045512.2) and assembled in silico.

      Lentogenic strains like LaSota have been used for more than 70 years of vaccination in avian
      populations and have proven to be safe and with a remarkable naturally attenuated viral
      activity. In fact, studies have shown that the insertion of foreign genes into the NDV genome
      leads to a further reduction of pathogenicity in birds. Furthermore, the rNDV is not excreted
      in feces and therefore not transmitted from bird to bird. Safety tests with avian rNDV
      vaccines have shown that doses 10 times higher than the dose suggested in this study are not
      associated with any pathogenicity.

      A rNDV vaccine against SARS-CoV and other emerging infections had been proposed. It has been
      demonstrated that a rNDV vector expressing the S-protein in the SARS-CoV coronavirus is
      capable of developing protective immunity without safety concerns when administered to
      African green monkeys by the intranasal route.

      It has been reported that rNDV injected by the IV route in non-human primates (Macaca
      fascicularis) was not associated with any severe disease or abnormalities in hematological or
      biochemical lab values.

      Recently, in the context of the COVID-19 pandemic, a vaccine based on a S-protein expressing
      viral vector of the Newcastle Disease virus (NDV) has been studied using both a wild type and
      a pre-fusion membrane-anchored vector format. These studies were performed in mice and
      hamster models with two administrations of the vaccine. The tested vaccines induced high
      levels of neutralizing antibodies when administered by the intramuscular route. Notably,
      these vaccine prototypes protected mice against a mouse-adapted SARS-CoV-2 challenge: neither
      viral load nor viral antigen were detected in the lungs.

      To produce the rNDV, a cell line is transfected by plasmids that express the whole viral
      genome that contains the gene in question. The clone of the whole NDV genome is transfected
      with helper plasmids that code for the viral proteins N, P and L under the control of the
      bacteriophage T7 RNA-polymerase promoter. The chimeric virus is obtained from the culture and
      propagated in chicken embryo SPF of 10 days of age, until the original vaccine virus is
      generated.

      The vaccine has been formulated for intranasal and intramuscular administration.

      In our study, ninety healthy volunteers with no history of COVID-19, vaccination against
      SARS-CoV-2 or an activity associated with a higher risk of exposure to SARS-CoV-2 will be
      assigned sequentially into one of nine treatment groups at a single research site in Mexico
      City.

      These treatment groups correspond to three different doses and three different schemes of
      administration. All these schemes foresee two vaccine administrations separated by 21 days.
      3rd administration by the intramuscular route to all the volunteers who agree to participate
      (see "Arms and Interventions").

      Patients will be followed for efficacy and safety measurements. Efficacy will be measured by
      circulating and neutralizing IgG and IgM antibodies against the S protein of SARS-CoV-2, IgA
      titers in nasal mucosa and cytokine-mediated T cell responses. Patient safety will be
      monitored by the collection of information on adverse events and safety laboratory
      assessments (mainly hematology and blood chemistry).

      The first intervention for each treatment group will be administered in a sequential way to
      eighteen sentinel subjects. Once all sentinel subjects have received the first intervention
      and the Safety Data Monitoring Board has determined that safety conditions have been met, the
      study will proceed to enroll the rest of the subjects until a total of 90 participants is
      reached.

      Statistical tests will be applied to each treatment group with similar baseline
      characteristics. For continuous variables Student's t distribution and ANOVA will be used to
      compare mean values, while chi-square and Fisher´s exact test will be used to assess
      categorical values.

      There are three working hypotheses to be tested, one for each scheme of administration. They
      can be consolidated as follows : The recombinant anti-SARS-CoV-2 vaccine based on a viral
      vector (rNDV) administered [two times by the intramuscular route / two times by the
      intranasal route / the first by the intranasal route and the second by the intramuscular
      route] is safe (i.e. an acceptable low profile or reactogenicity: low frequency of
      mild-to-moderate and no severe local or systemic adverse reactions) and induces a humoral and
      cellular immune response against SARS-CoV-2 similar (or greater) to that measured in sera
      from naturally-acquired COVID-19 convalescent individuals.
    

Intervention name(s): Recombinant NDV Vectored Vaccine for SARS-CoV-2
Intervention type(s): Biological
Intervention description(s): Recombinant Newcastle Disease Virus Vectored Vaccine for SARS-CoV-2
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Patients will be assigned in the order they enter the study into nine treatment groups according to dose and route of administration.
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Newcastle Disease Virus; rNDV; COVID-19; SARS-Cov-2 Vaccine; COVID-19 Vaccine