3. Bottlenecks in COVID-19 vaccine development
In the past decade a number of sporadic efforts have been made to
develop vaccines against human CoVs, but lack of cross-protection
rendered by these vaccines due to their extensive sequence diversity has
thwarted the progress (Graham et al., 2013). Also, there is the
possibility of transmission of SARS-CoV or SARS-CoV-2 from animal
reservoirs. Thus, the concentration of focus on additional structural
proteins, other than spike (S) protein, and conserved epitopes is needed
to develop a vaccine which can induce broader heterologous and
cross-protective immunity against CoVs within beta-CoV lineage (Saif,
2020). Elucidation of the biological characteristics of any newly
emerged virus is instrumental in establishing potential treatments and
preventive strategies (Gillim-Ross and Subbarao, 2006). The detailed
biological characteristics of SARS-CoV-2 is still unknown and whether it
infects only respiratory tract or both respiratory and intestinal tracts
is yet to be established. In the latter case oro-nasal vaccine followed
by parenteral S protein based booster strategy can be optimum to prevent
respiratory and enteric infections along with cessation of fecal and
nasal shedding of viruses (Saif, 2020). Another important aspect of
biological characteristics of SARS-CoV-2 is the route of dissemination
to lungs which is not clear yet. If the lungs get targeted after an
upper respiratory tract infection then intranasal live or attenuated
vaccine can effectively induce local immunity which could protect the
upper as well as lower respiratory tracts and reduce nasal shedding.
However, if the lungs are infected via viraemia, then parental vaccine
can effectively elicit sufficient virus neutralizing (VN) antibodies in
serum to block viraemia which in turn prevents lung infection and virus
shedding (Saif, 2020). Furthermore, contribution of cytopathic effect of
the virus and immunopathology in the pathogenesis of SARS-CoV infections
is unclear which has a direct bearing on the vaccine strategy to be
adopted for better protection (Gillim-Ross and Subbarao, 2006). The
undesired immunopotentiation in the form of eosinophilic infiltration or
increased infectivity was observed following challenge infections after
immunizations with whole virus vaccines or even complete spike protein
vaccines (Jiang et al., 2012). This constitutes another major obstacle
in the development of SARS CoV vaccines.
Though, the vaccine candidates induce serum VN antibodies and systemic
cell-mediated immune response in animal models, the correlates of
immunity to COVID-19 in humans are still unknown (Saif, 2020). However,
in face of the ongoing COVID-19 epidemic vaccine development can be
initiated in absence of knowledge on the correlates of immunity by
utilizing the strategies developed for vaccine targeting of other
viruses. It is because both mucosal and humoral immunity confers
protection against most of the respiratory viral infections; however,
the role of cell mediated immunity in such protection has not been
established yet (Gillim-Ross and Subbarao, 2006). Antibody dependent
enhancement (ADE) of CoV infections following vaccination is also a
major concern for vaccine development against COVID-19. Though, the
mechanism behind ADE is not yet clear it is supposed to be due to
sub-neutralizing antibodies which do not have the capacity to completely
neutralize viral particles but instead cause enhanced uptake and spread
of the viruses by entering Fc receptor expressing cells (Wan et al.,
2020; Gillim-Ross and Subbarao, 2006). Currently we do not have any
approved treatment or vaccine against the deadly infections of CoVs,
including COVID-19 because of lack of interest among pharmaceutical
companies and lack of sustained government funding for vaccine
development due to disappearance of SARS and decline of MERS (Cyranoski
et al., 2020; Saif, 2020). Compared to the traditional childhood and
adult vaccines the development of vaccines against SARS CoVs for global
health security or biodefense are considered less profitable and it has
also been the major reason for the lack of interest shown by major
multi-national pharmaceutical companies for commercial vaccine
development (Chen et al., 2020). The outbreak scenarios are generally
short lived and the proportion of people affected is small which does
not constitute a significant vaccine market. Furthermore, by the time a
new vaccine is available, there might not be any patients available for
clinical trials and also no significant market (Dhama et al., 2020). The
possible vaccine for COVID-19 must be made available for potential
stockpiling because it may not be available for the current pandemic
(Chen et al., 2020). However, extensive geographical spread and
involvement of large number of people with rapidly increasing cases have
sensitized the governments and pharmaceutical companies worldwide to
reinforce their efforts against the control of COVID-19. Another aspect
of COVID-19 infection is nasal shedding of virus and further
transmission in the population which can’t be prevented without mucosal
immunity. The possible vaccine should not only prevent the deaths but
also the nasal virus shedding by boosting mucosal immunity which is
generally short-lived and requires multiple booster vaccinations (Saif,
2020). Another bottleneck in the process of vaccine development against
COVID-19 is the lack of suitable animal model to test the vaccine
efficacy and safety. None of the animal models appropriately mimic the
human COVID-19 infection and the potential correlates of infection
(Saif, 2020). Though, ferrets mimic the SARS pathogenesis well in humans
(Roper and Rehm, 2009) their limitation is less well characterised
immune system. On the other hand if SARS susceptible pigs are
susceptible to SARS-CoV-2 too, they are supposed to be potentially
better model because of their close resemblance to humans in terms of
their outbred nature, physiology, metabolism, respiratory system, and
immune responses (Vlasova et al., 2016).