In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.
Challenges
Although the development of a vaccine to protect against SARS-CoV-2 infection has progressed at an unprecedented rate and produced an impressive volume of candidates for testing, many challenges lie ahead. The prior knowledge gained after SARS-CoV-1 was first discovered in 2003, and the subsequent emergence of MERS-CoV in 2012 provided a significant jumpstart, but the progress of SARS-CoV-2 vaccine development has already far outstripped the point of the blueprint created before COVID-19 became a pandemic. While a variety of platforms are simultaneously being innovated or adapted, they each have strengths and limitations, many of which relate to the delicate balance between safety and immunogenicity. Many shortcuts have been taken and will continue to be taken due to the urgency of the ongoing COVID-19 pandemic, but significant concerns need to be addressed. One such concern involves the accumulating data supporting the initial assessment that COVID-19 is disproportionately severe in older adults. In conjunction with the large body of work related to immune senescence, these findings indicate that vaccine design should take into consideration the impact of aging on vaccine efficacy (Nikolich-Žugich, 2018). Furthermore, questions remain regarding the possibility of antibody-dependent enhancement of COVID-19, with in vitro experiments, animal studies, and two studies of COVID-19 patients supporting this possibility (Cao, 2020, Tetro, 2020, Zhang et al., 2020a, Zhao et al., 2020a). Assuming vaccine candidates that can safely induce protective immune responses are identified, additional major hurdles will be the production and dissemination of a vaccine. For some types of vaccines, large-scale production will not be as much of an issue, and infrastructure already in place to produce current Good Manufacturing Practice (cGMP)-quality biologics can be repurposed, but this will only be applicable to a subset of the candidates (Thanh Le et al., 2020). In order to address the urgent need and stem the COVID-19 pandemic, regulatory agencies need to continue to support rapid testing and progression of vaccine candidates, companies need to disseminate important findings directly and openly, and researchers need to investigate correlates of protection using in-depth immune monitoring of patients with a broad range of clinical presentations and clinical trial participants. The newly announced Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) is designed to bring together numerous governmental and industry entities to help address this need.
Concluding Remarks
The rapid spread of SARS-CoV-2 and the unprecedented nature of COVID-19 has demanded an urgency in both basic science and clinical research, and the scientific community has met that call with remarkable productivity. Within months, there has been a significant generation of scientific knowledge that has shed some light on the immunology of SARS-CoV-2 infections. Studies of past coronavirus outbreaks involving SARS-CoV-1 and MERS-CoV have provided a foundation for our understanding. The pathology of severe cases of COVID-19 does indeed resemble certain immunopathologies seen in SARS-CoV-1 and MERS-CoV infections, like CRS.However, in many other ways, immune responses to SARS-CoV-2 are distinct from those seen with other coronavirus infections. The emerging epidemiological observation that significant proportions of individuals are asymptomatic despite infection not only reflects our current understanding that SARS-CoV-2 has a longer incubation period and higher rate of transmission than other coronaviruses, but also speaks to significant differences in the host immune response. Therefore, it is imperative that immune responses against SARS-CoV-2 and mechanisms of hyperinflammation-driven pathology are further elucidated to better define therapeutic strategies for COVID-19. Here, we reviewed the recent literature and highlighted hypotheses that interrogate mechanisms for viral escape from innate sensing, for hyperinflammation associated with CRS and inflammatory myeloid subpopulations, for lymphopenia marked by T cell and NK cell dysfunction, and for correlates of protection and their duration, among others. Still, additional studies are needed to address how these immune differences across patients or between different types of coronavirus infections dictate who succumbs to disease and who remains asymptomatic. Existing studies of SARS-CoV-1 and MERS-CoV and ongoing studies of SARS-CoV-2 will likely provide a robust framework to fulfill that unmet need.
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