Comparative evaluation of two severe acute respiratory syndrome (SARS) vaccine candidates in mice challenged with SARS coronavirus

Abstract

Two different severe acute respiratory syndrome (SARS) vaccine strategies were evaluated for their ability to protect against live SARS coronavirus (CoV) challenge in a murine model of infection. A whole killed (inactivated by b-propiolactone) SARS-CoV vaccine and a combination of two adenovirus-based vectors, one expressing the nucleocapsid (N) and the other expressing the spike (S) protein (collectively designated Ad S/N), were evaluated for the induction of serum neutralizing antibodies and cellular immune responses and their ability to protect against pulmonary SARS-CoV replication. The whole killed virus (WKV) vaccine given subcutaneously to 129S6/SvEv mice was more effective than the Ad S/N vaccine administered either intranasally or intramuscularly in inhibiting SARS-CoV replication in the murine respiratory tract. This protective ability of the WKV vaccine correlated with the induction of high serum neutralizing-antibody titres, but not with cellular immune responses as measured by gamma interferon secretion by mouse splenocytes. Titres of serum neutralizing antibodies induced by the Ad S/N vaccine administered intranasally or intramuscularly were significantly lower than those induced by the WKV vaccine. However, Ad S/N administered intranasally, but not intramuscularly, significantly limited SARS-CoV replication in the lungs. Among the vaccine groups, SARS-CoV-specific IgA was found only in the sera of mice immunized intranasally with Ad S/N, suggesting that mucosal immunity may play a role in protection for the intranasal Ad S/N delivery system. Finally, the sera of vaccinated mice contained antibodies to S, further suggesting a role for this protein in conferring protective immunity against SARS-CoV infection. (Marra et al., 2003;Rota et al., 2003) and by experimental infection of macaques to fulfil Koch's postulates . 0008-1579 G 2006 SGM Printed in Great BritainCurrently, there is no effective treatment for SARS. Prevention through contact-reduction or transmission-blocking measures has been the only means available to modify the devastating impact of this illness. Prevention through vaccination would be an attractive alternative that is less reliant on individual case detection to be effective. No vaccines are currently licensed for any of the human CoVs, but effective vaccines have been produced for some animal CoVs, such as certain strains of Infectious bronchitis virus (poultry), Bovine coronavirus and Canine coronavirus (Cavanagh, 2003;Enjuanes et al., 1995;Pratelli et al., 2003;Saif, 2004;Takamura et al., 2002). Individuals convalescing from SARS develop high titres of neutralizing antibodies (Tan et al., 2004) and the appearance of antibodies coincides with the onset of resolution of SARS pneumonia Woo et al., 2004). Thus, there is some optimism that an effective vaccine against SARS-CoV may also be possible.Coronavirus spike (S) proteins have long been known to be a major determinant in coronavirus pathogenesis, given that this viral protein interacts with cellular receptors as well as con...

Severe acute respiratory syndrome vaccine efficacy in ferrets: whole killed virus and adenovirus-vectored vaccines

“…Our preliminary studies showed clinical signs, viral replication and lung pathology in ferrets infected with SARS-CoV reflecting pathogenesis in humans ; we therefore decided to evaluate and compare our two SARS vaccine candidates (WKV and Ad expressing S and N protein) in a single trial in the ferret model (Kobinger et al, 2007). This is the first report of two SARS vaccine formats tested directly against each other in both mice (See et al, 2006) and ferrets. …”

“…N protein has been shown to generate CoV-specific CD8 + T cells (Boots et al, 1991;Seo et al, 1997; Stohlman et al, 1993 Stohlman et al, , 1995; it also provides protection in animals in response to infection by animal CoV (Collisson et al, 2000;Seo et al, 1997). In addition, vaccination with SARS N protein decreased replication of a vaccinia virus expressing SARS N protein in mice (Kim et al, 2004).The SARS Accelerated Vaccine Initiative (SAVI) (Finlay et al, 2004) described the first head-to-head comparison of a WKV SARS-CoV vaccine and a combination of attenuated Ad expressing either S or N glycoproteins (Ad S/N) for their ability to protect against live SARS-CoV challenge in a mouse model (See et al, 2006). In the mouse model, the WKV vaccine, in the presence or absence of alum adjuvant, provided protection against live SARS-CoV challenge by the induction of high levels of neutralizing antibodies and reduced SARS-CoV load in the respiratory tract compared with mock-vaccinated mice.…”

“…The blots were processed for detection using the ECL Advanced Western Blotting Detection kit. Recombinant SARSCoV N protein expressed in Escherichia coli and a truncated S protein (amino acids 318-510) expressed stably in a HEK 293 cell line, as previously described (See et al, 2006), were also used as antigens.RT-PCR assay for SARS-CoV RNA. Fifty microlitres of lung homogenate was placed in TRIzol reagent and processed as previously described (Hogan et al, 2004).…”

How Prepared Are We to Control Severe Acute Respiratory Syndrome in Future

“…Subsequent studies demonstrated that a sub lingual immunization can prevent the viral vector entry into the brain (Shim et al, 2012). Also, an intranasal route of vaccination was shown to protect mice from SARS-CoV challenge better than an intramuscular delivery of the same vaccine (See et al, 2006;Hu et al, 2007). Expression of full length S protein is shown to result in enhanced hepatitis or infection whereas, expression of just the ectodomain of S protein eliminated infection enhancement (Weingartl et al, 2004;Yang et al, 2005b).…”

“…(Lin et al, 2007). Hypersensitive appropriate animal model (See et al, 2008) reaction upon post-immunization viral challenge in mice (Kam et al, 2007;Tseng et al, 2012) Recombinant vector Disease exacerbation upon SARS-CoV Protective in mice, ferrets, monkeys, Vaccines (Adenovirus, challenge in some cases (Czub et al, 2005) hamsters (Bukreyev et al, 2004; Poxvirus or recombinant) See et al, 2006;Napoli et al, 2007;See et al, 2008) …”