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).