Subunit and inactivated SARS vaccinations
It has been found that inactivated SARS vaccinations induce significant titers of spike-specific neutralising antibodies. However, few research have examined whether inactivated SARS-CoV virions give protection against virus challenge. Mice inoculated twice with a prospective SARS-CoV vaccine generated by a two-step inactivation technique including sequential formaldehyde and U.V. inactivation developed high antibody titres and high levels of neutralising antibodies against the SARS-CoV spike protein. 41 In addition, the vaccination provided protective immunity, as evidenced by the suppression of SARS-CoV replication in the respiratory tracts of mice following intranasal challenge with SARS-CoV. The protection of mice was associated with neutralising and anti-SARS-CoV S antibody titers.
Using an inactivated SARS-CoV vaccination with beta-propiolactone in mice yielded comparable results.
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42 Moreover, two Chinese research groups have established the efficacy of inactivated SARS vaccinations in rhesus monkeys. 43,44 A recombinant polypeptide containing the N-terminal portion of the spike glycoprotein may produce neutralising antibodies and protective responses in mice.
2 whole-virus inactivated vaccinations
Initially, SARS virus was cultivated in cell culture under biosafety level (BSL)-3 conditions and subsequently inactivated using formaldehyde, beta-propriolactone, UV light, or a combination of these. In animal trials, these initial inactivated whole viral vaccinations induced low neutralising antibody titers and accelerated lung virus clearance, but did not completely prevent infection. 11 In a phase 1 clinical trial, a small number of human participants received this type of inactivated vaccination, which was found to elicit neutralising antibodies. 12 Although no obvious safety concerns were discovered, the participants were not exposed to the SARS virus; hence, the possibility of this vaccination exacerbating lung immune-pathology is unknown.
Notably, when challenged with SARS virus, animals inoculated with comparable inactivated vaccinations exhibited significant lung eosinophilic immunopathology.
13–16 This lung pathology was aggravated when alum adjuvant was added to SARS vaccinations in an attempt to boost their immunogenicity. 9 Despite the ability of inactivated vaccines with alum adjuvant to limit virus replication in young animals, they failed to do so in older animals, whose usage was associated with significant lung eosinophilic disease post-challenge. 13 This conclusion is especially worrisome, given that the elderly are a primary target population for SARS vaccinations, as they are at the highest risk for complications and death. If the animal studies apply to people, this indicates that inactivated vaccines may not only fail to protect the elderly, but may also increase their risk of developing a serious illness if exposed to the SARS virus.
Mice inoculated with Venezuelan equine encephalitis virus replicon particles expressing the SARS nucleocapsid protein also exhibited lung eosinophilic disease.
17 Similarly, mice inoculated with vaccinia virus producing the SARS nucleocapsid protein developed a severe pneumonia marked by elevated Th2 and Th1 cytokines, decreased IL-10 and TGF-beta, thickening of the alveolar epithelium, and lung infiltration by eosinophils, lymphocytes, and neutrophils. 15 Inactivated whole viral formulations are therefore poor prospects for safe and efficacious SARS vaccines due to their poor immunogenicity, difficulty of BSL-3 production, poor efficacy in the elderly, and danger of illness exacerbation due to eosinophilic lung immunopathology.
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