"Vaccine technology has significantly evolved in the last decade, including the development of several RNA and DNA vaccine candidates, licensed vectored vaccines (e.g., Ervebo, a vesicular stomatitis virus [VSV]-vectored ebolavirus vaccine, licensed in the European Union), recombinant protein vaccines (e.g., Flublok, an influenza virus vaccine made in insect cells, licensed in the United States), and cell-culture-based vaccines (e.g., Flucelvax, an influenza virus vaccine made in mammalian cells). SARS-CoV-2 was identified in record time, and its genomic sequence was swiftly made widely available by Chinese researchers (Wu et al., 2020, Zhou et al., 2020, Zhu et al., 2020). In addition, we know from studies on SARS-CoV-1 and the related MERS-CoV vaccines that the S protein on the surface of the virus is an ideal target for a vaccine. In SARS-CoV-1 and SARS-CoV-2, this protein interacts with the receptor ACE2, and antibodies targeting the spike can interfere with this binding, thereby neutralizing the virus (Figure 1). The structure of the S protein of SARS-CoV-2 was solved in record time at high resolution, contributing to our understanding of this vaccine target (Lan et al., 2020a, Wrapp et al., 2020). Therefore, we have a target antigen that can be incorporated into advanced vaccine platforms.
Figure 1. Overview of Potential SARS-CoV-2 Vaccine Platforms
The structure of a coronavirus particle is depicted on the left, with the different viral proteins indicated. The S protein is the major target for vaccine development. The spike structure shown is based on the trimeric SARS-CoV-1 spike (PDB: 5XL3). One trimer is shown in dark blue, and the receptor binding domain, a main target of neutralizing antibodies, is highlighted in purple. The other two trimers are shown in light blue. SARS-CoV-2 vaccine candidates based on different vaccine platforms have been developed, and for some of them, pre-clinical experiments have been initiated. For one mRNA-based candidate, a clinical trial recently started to enroll volunteers shortly (ClinicalTrials.gov: NCT04283461). However, many additional steps are needed before these vaccines can be used in the population, and this process might take months, if not years. 1For some candidates, cGMP processes have already been established. 2Clinical trial design might be altered to move vaccines through clinical testing quicker.
Several vaccines for SARS-CoV-1 were developed and tested in animal models, including recombinant S-protein-based vaccines, attenuated and whole inactivated vaccines, and vectored vaccines (Roper and Rehm, 2009). Most of these vaccines protect animals from challenge with SARS-CoV-1, although many do not induce sterilizing immunity. In some cases, vaccination with the live virus results in complications, including lung damage and infiltration of eosinophils in a mouse model (e.g., Bolles et al., 2011, Tseng et al., 2012) and liver damage in ferrets (e.g., Weingartl et al., 2004). In another study, vaccination with inactivated SARS-CoV-1 led to enhancement of disease in one NHP, whereas it protected 3 animals from challenge (Wang et al., 2016). The same study identified certain epitopes on the S protein as protective, whereas immunity to others seemed to be enhancing disease. However, in almost all cases, vaccination is associated with greater survival, reduced virus titers, and/or less morbidity compared with that in unvaccinated animals. Similar findings have been reported for MERS-CoV vaccines (Agrawal et al., 2016, Houser et al., 2017). Therefore, whereas vaccines for related coronaviruses are efficacious in animal models, we need to ensure that the vaccines, which are developed for SARS-CoV-2, are sufficiently safe.
Another consideration for effective coronavirus vaccine development might be waning of the antibody response. Infection with human coronaviruses does not always induce long-lived antibody responses, and re-infection of an individual with the same virus is possible after an extended period of time (but only in a fraction of individuals and resulting in mild or no symtpoms), as shown in human challenge studies (Callow et al., 1990). Antibody titers in individuals that survived SARS-CoV-1 or MERS-CoV infections often waned after 2–3 years (Liu et al., 2006, Wu et al., 2007) or were weak initially (Choe et al., 2017). Despite that, re-infections are unlikely in the short term. Of note, re-infections after days of recovery have been reported recently but appear to be the consequences of false negative test results (Lan et al., 2020b). However, they could happen when humoral immunity wanes over months and years. An effective SARS-CoV-2 vaccine will need to overcome these issues to protect in a scenario in which the virus becomes endemic and causes recurrent seasonal epidemics.
SARS-CoV-2 infection causes the most severe pathology in individuals above 50 years of age. The reason for this is not clear, but many viral infections have milder manifestations in naive younger individuals than in naive older individuals. Because older individuals are more affected, it will be important to develop vaccines that protect this segment of the population. Unfortunately, older individuals typically respond less well to vaccination because of immune senescence (Sambhara and McElhaney, 2009). For influenza, which is problematic for older adults, specific formulations for this segment of the population include more antigen or an adjuvant (DiazGranados et al., 2013, Tsai, 2013). Protection in older individuals appears to require higher neutralization titers against influenza virus than in younger individuals (Benoit et al., 2015), and this issue might need to be addressed for SARS-CoV-2. If vaccination in older individuals is not effective, they could still benefit indirectly if vaccination is able to stop transmission of the virus in younger individuals.
Only a small number of SARS-CoV-1 vaccines made it to phase I clinical trials before funding dried up because of eradication of the virus from the human population through non-pharmaceutical interventions when case numbers were still small. Results from these trials, performed with an inactivated virus vaccine and a spike-based DNA vaccine, are encouraging because the vaccines were safe and induced neutralizing antibody titers (Lin et al., 2007, Martin et al., 2008). Some neutralizing monoclonal antibodies isolated against SARS-CoV-1, like CR3022 (ter Meulen et al., 2006, Tian et al., 2020), can cross-react to the receptor binding domain of SARS-CoV-2. This suggests that SARS-CoV-1 vaccines might cross-protect against SARS-CoV-2. However, because these vaccines have not been developed further than phase I, they are currently not available for use. Vaccines against MERS-CoV, also targeting the MERS-CoV S protein, are in pre-clinical and clinical development, including vaccines based on modified vaccinia Ankara vectors, adenovirus vectors, and DNA-based vaccines, and several of them are supported by the Coalition for Epidemic Preparedness Innovation (CEPI) (Yong et al., 2019). However, it is unlikely that MERS-CoV vaccines induce strong cross-neutralizing antibodies to SARS-CoV-2 because of the phylogenetic distance between the two viruses. Nevertheless, we can still learn a lot from these vaccines about how to move forward with SARS-CoV-2 vaccine design (Pallesen et al., 2017).
The Current Pipeline for SARS-CoV-2 Vaccines
The development of vaccines for human use can take years, especially when novel technologies are used that have not been extensively tested for safety or scaled up for mass production. Because no coronavirus vaccines are on the market and no large-scale manufacturing capacity for these vaccines exists as yet (Table 1), we will need to build these processes and capacities. Doing this for the first time can be tedious and time consuming (Figure 1). CEPI has awarded funds to several highly innovative players in the field, and many of them will likely succeed in eventually making a SARS-CoV-2 vaccine. However, none of these companies and institutions have an established pipeline to bring such a vaccine to late-stage clinical trials that allow licensure by regulatory agencies, and they do not currently have the capacity to produce the number of doses needed. An mRNA-based vaccine, which expresses target antigen in vivo in the vaccinee after injection of mRNA encapsulated in lipid nanoparticles, co-developed by Moderna and the Vaccine Research Center at the National Institutes of Health, is currently the furthest along, and a phase I clinical trial recently started (ClinicalTrials.gov: NCT04283461). Curevac is working on a similar vaccine but is still in the pre-clinical phase. Additional approaches in the pre-clinical stage include recombinant-protein-based vaccines (focused on the S protein, e.g., ExpresS2ion, iBio, Novavax, Baylor College of Medicine, University of Queensland, and Sichuan Clover Biopharmaceuticals), viral-vector-based vaccines (focused on the S protein, e.g., Vaxart, Geovax, University of Oxford, and Cansino Biologics), DNA vaccines (focused on the S protein, e.g., Inovio and Applied DNA Sciences), live attenuated vaccines (Codagenix with the Serum Institute of India, etc.), and inactivated virus vaccines (Figure 1; Table 1). All of these platforms have advantages and disadvantages (Table 1), and it is not possible to predict which strategy will be faster or more successful. Johnson & Johnson (J&J) (Johnson & Johnson, 2020) and Sanofi (2020) recently joined efforts to develop SARS-CoV-2 vaccines. However, J&J is using an experimental adenovirus vector platform that has not yet resulted in a licensed vaccine. Sanofi’s vaccine, to be made using a process similar to the process used for their approved Flublok recombinant influenza virus vaccine (Zhou et al., 2006), is also months, if not years, from being ready for use in the human population."
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