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].