A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response upon Challenge

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) is an important emerging virus that is highly pathogenic in aged populations and is maintained with great diversity in zoonotic reservoirs. While a variety of vaccine platforms have shown efficacy in young-animal models and against homologous viral strains, vaccine efficacy has not been thoroughly evaluated using highly pathogenic variants that replicate the acute end stage lung disease phenotypes seen during the human epidemic. Using an adjuvanted and an unadjuvanted doubleinactivated SARS-CoV (DIV) vaccine, we demonstrate an eosinophilic immunopathology in aged mice comparable to that seen in mice immunized with the SARS nucleocapsid protein, and poor protection against a nonlethal heterologous challenge. In young and 1-year-old animals, we demonstrate that adjuvanted DIV vaccine provides protection against lethal disease in young animals following homologous and heterologous challenge, although enhanced immune pathology and eosinophilia are evident following heterologous challenge. In the absence of alum, DIV vaccine performed poorly in young animals challenged with lethal homologous or heterologous strains. In contrast, DIV vaccines (both adjuvanted and unadjuvanted) performed poorly in aged-animal models. Importantly, aged animals displayed increased eosinophilic immune pathology in the lungs and were not protected against significant virus replication. These data raise significant concerns regarding DIV vaccine safety and highlight the need for additional studies of the molecular mechanisms governing DIV-induced eosinophilia and vaccine failure, especially in the more vulnerable aged-animal models of human disease.

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“…Similarly, laboratory animals administered alum-adjuvanted whole-virus SARS-CoV vaccine and subsequently challenged with infectious virus experienced enhanced disease and immunopathology comprised of eosiniophilic infiltration and Th2-mediated inflammatory alveolar damage [21], similar to immunopathologic lung reactions found in infants and animals challenged with respiratory syncytial virus (RSV) [22,23]. A double-inactivated SARS-CoV (formalin and ultraviolet radiation) was also shown to elicit eosinophilic and immunoenhancing pathology, as well as poor protection, especially in aged animals, suggesting the possibility that aged humans (a desired target population for the vaccine) may be particularly vulnerable to vaccine-induced effects [24]. Further studies showed that a Venezuelan equine encephalitis vector containing the SARS nucleocapsid (NP) gene also elicited eosinophilic immunopathology in BALB/c mice after challenge without any noticeable protection [25].…”