Severe Acute Respiratory Syndrome-Associated Coronavirus Vaccines Formulated with Delta Inulin Adjuvants Provide Enhanced Protection while Ameliorating Lung Eosinophilic Immunopathology

Abstract

Although the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) epidemic was controlled by nonvaccine measures, coronaviruses remain a major threat to human health. The design of optimal coronavirus vaccines therefore remains a priority. Such vaccines present major challenges: coronavirus immunity often wanes rapidly, individuals needing to be protected include the elderly, and vaccines may exacerbate rather than prevent coronavirus lung immunopathology. To address these issues, we compared in a murine model a range of recombinant spike protein or inactivated whole-virus vaccine candidates alone or adjuvanted with either alum, CpG, or Advax, a new delta inulin-based polysaccharide adjuvant. While all vaccines protected against lethal infection, addition of adjuvant significantly increased serum neutralizing-antibody titers and reduced lung virus titers on day 3 postchallenge. Whereas unadjuvanted or alum-formulated vaccines were associated with significantly increased lung eosinophilic immunopathology on day 6 postchallenge, this was not seen in mice immunized with vaccines formulated with delta inulin adjuvant. Protection against eosinophilic immunopathology by vaccines containing delta inulin adjuvants correlated better with enhanced T-cell gamma interferon (IFN-␥) recall responses rather than reduced interleukin-4 (IL-4) responses, suggesting that immunopathology predominantly reflects an inadequate vaccine-induced Th1 response. This study highlights the critical importance for development of effective and safe coronavirus vaccines of selection of adjuvants based on the ability to induce durable IFN-␥ responses. IMPORTANCECoronaviruses such as SARS-CoV and Middle East respiratory syndrome-associated coronavirus (MERS-CoV) cause high case fatality rates and remain major human public health threats, creating a need for effective vaccines. While coronavirus antigens that induce protective neutralizing antibodies have been identified, coronavirus vaccines present a unique problem in that immunized individuals when infected by virus can develop lung eosinophilic pathology, a problem that is further exacerbated by the formulation of SARS-CoV vaccines with alum adjuvants. This study shows that formulation of SARS-CoV spike protein or inactivated whole-virus vaccines with novel delta inulin-based polysaccharide adjuvants enhances neutralizing-antibody titers and protection against clinical disease but at the same time also protects against development of lung eosinophilic immunopathology. It also shows that immunity achieved with delta inulin adjuvants is long-lived, thereby overcoming the natural tendency for rapidly waning coronavirus immunity. Thus, delta inulin adjuvants may offer a unique ability to develop safer and more effective coronavirus vaccines. The severe acute respiratory syndrome-associated coronavirus (SARS-CoV) was identified in 2003 when a series of fatal pneumonia cases started in Hong Kong (1, 2). SARS-CoV lung infection is characterized by a marked inflammatory cell infi...

Molecular Basis of Coronavirus Virulence and Vaccine Development

“…Intranasal vaccination with the RBD domain of the MERS-CoV S protein induced much stronger local mucosal immune responses in the lung than subcutaneous immunization (Ma et al, 2014a). Other studies showed that full-length monomeric or trimeric recombinant SARS-CoV and MERS-CoV S proteins are able to induce protective responses in mice (Honda-Okubo et al, 2015;Li et al, 2013) and the presentation of MERS-CoV full-length S protein as nanoparticles in combination with appropriate adjuvants elicits neutralizing antibodies in immunized mice (Coleman et al, 2014a).…”

“…To increase the duration of immune responses elicited by vaccines and to prevent the CoV-induced lung immunopathology observed after challenge or natural infection, the effects of adjuvants have been studied. In immunizations either with recombinant CoV S protein or with inactivated wholevirus vaccines, the effects of different adjuvants including alum, CpG, and Adva, a new delta-inulin-based polysaccharide adjuvant, were analyzed (Honda-Okubo et al, 2015). While all vaccines protected against lethal infection, addition of an adjuvant significantly increased serum neutralizing antibody titers and reduced lung virus titers on day 3 postchallenge.…”

Advax augments B and T cell responses upon influenza vaccination via the respiratory tract and enables complete protection of mice against lethal influenza virus challenge

“…Advax adjuvant comprises discoidal shape particles of 1-2 μm in diameter, formed by assembly of a series of lamellar crystalline sheets [23]. Adjuvantation of parenterally administered vaccines with Advax has shown to improve the immunogenicity and protective capacity of several vaccine candidates against hepatitis B, anthrax, severe acute respiratory syndrome (SARS) coronavirus, listeria and influenza [21,[24][25][26][27]. The exact mechanism by which Advax boosts immune responses upon parenteral administration is still under investigation [23].…”

Randomized controlled trial demonstrating the benefits of delta inulin adjuvanted immunotherapy in patients with bee venom allergy

“…19 Advax has been shown to provide enhanced vaccine immunogenicity and antigen sparing while having low reactogenicity. 20 It drives a strong T H 1 response that might help suppress any excess T H 2 bias in allergic patients. Notably, when formulated with Advax, vaccines against severe acute respiratory syndrome (SARS) were able to suppress eosinophilic lung pathology after SARS coronavirus infection, whereas this problem was aggravated by formulation of SARS vaccine with the TH2-biasing alum adjuvant.…”