9. Inactivated vaccines
Inactivated or killed viruses by chemical or physical approaches such as heat and formaldehyde are the alternative vaccine candidates that have been utilized to combat influenza, hepatitis A virus (HAV) and polio (IPV) [91, 92]. In this approach, viral particles no longer have the ability to reproduce and pathogenicity, although intact viral antigens with natural conformational structures are provided to induce antibody responses (Fig. 2) (Table 3). Unlike live attenuated vaccines, there is no safety concern about the return of pathogenic species in killed vaccines [93, 94]. At present, nine progressive clinical trials along with twelve further inactivated SARS-CoV2 vaccine candidates in preclinical stage are under investigation [52]. BBIBP- CorV is an inactivated vaccine candidate with aluminium hydroxide adjuvant against SARS-CoV2 that has been tested by Sinofarm company in China on a wide range of animal models and fortunately has shown promising results in inhumane mammals [95]. PiCoVacc is the other inactivated alum-based SARS-CoV2 vaccine by the Chinese Sinovac Biotech Ltd with confirmed preclinical outcomes that protects rhesus macaques against SARS-CoV2 complications [54]. Indeed, vaccination with PiCoVacc diminished viral RNA load and mitigates anti-S and anti-nucleocapsid antibodies-related immunopathology [54]. However, inactivated vaccines are often associated with adjuvants and require repeated doses to induce protective immune responses [8]. Besides, the use of alum adjuvant greatly limits the administration of respiratory route of vaccines, and it is unclear how long intramuscular injections of BBIBP-CorV and PiCoVacc vaccines can provide mucosal immunity through the delivery of serum antibodies to the lungs. Moreover, the cytotoxic CD8+ T cell responses, which is important for coping with COVID-19, is not well stimulated after inactivated vaccines [8, 95]. Similar experiences with respiratory syncytial virus (RSV) and SARS-CoV inactivated vaccines exhibited disease exacerbation, probably due to the dominance of Th2 response and eosinophil accumulation especially in old patients [96, 97]. The use of BBIBP- CorV and PiCoVacc vaccines did not worsen the pulmonary side effects in animal models over the course of one week, although alum stimulates Th2 responses, which makes their use questionable. Therefore, the use of Th1 stimulant adjuvants such as modified alum, may alleviate the problem of worsening pulmonary complications in relation to these vaccines [98]. CoronaVac by Chinese Sinovac Biotech company is the other leading inactivated vaccine with alum adjuvant that has started phase III clinical trials in Indonesia, Brazil and Turkey from July [52]. The BBV152 is a whole virion inactivated SARS-COV2 vaccine with aluminium hydroxide gel (Algel) or a novel TLR7/8 agonist adsorbed Algel formulation has shown promising results in the preclinical phase in mice, rats and rabbits. Studies have shown that utilizing two different concentrations of this vaccine in all three specious induced effective neutralizing antibody responses. Also, the formulation containing TLR7/8 agonist primed Th1-biased antibody responses with elevated IgG2a and increased the response of specific IFNγ-producing CD4+ T lymphocytes [99]. The vaccine has now entered the phase III clinical trials, but is not yet allowed for limited or emergency applications. Other inactivated vaccine candidates are in the initial stages of clinical trials [52].