Trends in Immunology
Volume 42, Issue 2, February 2021, Pages 94-103
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Opinion
Complement Factors in COVID-19 Therapeutics and Vaccines

https://doi.org/10.1016/j.it.2020.12.002Get rights and content

Highlights

  • Complement has been implicated in playing some role in severe COVID-19 pathogenesis. However, the evidence to support this is largely inferred from case–control studies.

  • The potential protective role of complement has been largely ignored, which might contribute to innate and adaptive immunity against SARS-CoV-2 infection.

  • Immunity to many pathogens relies on complement to enhance antibody-mediated neutralization and mediate phagocytosis and lysis. These mechanisms might also contribute to immunity against SARS-CoV-2 infection, and complement might be potentially exploited in antibody-based therapeutics and vaccines.

  • Careful selection of vaccine adjuvants and epitopes included in vaccine constructs can influence whether vaccine-induced antibodies activate complement.

  • Mutations in monoclonal antibodies can be used to promote hexamer formation between antibodies, which can significantly improve complement binding and activation.

Complement is integral to a healthy functioning immune system and orchestrates various innate and adaptive responses against viruses and other pathogens. Despite its importance, the potential beneficial role of complement in immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been overshadowed by reports of extensive complement activation in severe coronavirus disease 2019 (COVID-19) patients. Here, we hypothesize that complement may also have a protective role and could function to enhance virus neutralization by antibodies, promote virus phagocytosis by immune cells, and lysis of virus. These functions might be exploited in the development of effective therapeutics and vaccines against SARS-CoV-2.

Section snippets

Beyond Directly Neutralizing Antibodies

The COVID-19 pandemic is a major global concern as there is no pre-existing immunity to the novel causative agent, SARS-CoV-2, and severe disease often has a poor prognosis. Considerable efforts are underway to develop effective interventions including vaccines and passive immunization therapies using purified immunoglobulins and recombinant monoclonal antibodies (MAbs). These strategies largely focus on the virus spike (S) protein (see Glossary), which interacts via the receptor-binding domain

Complement in Innate and Adaptive Immunity

Human complement is an organized system comprising >30 serum proteins; many of which contain protease activity enabling one complement protein to activate another in a sequential cascade [2]. This process can be initiated by three distinct pathways. The classical pathway is an adaptive immune response activated by interactions between complement protein C1q and antibodies bound to antigens (IgM, IgG1, and IgG3 have the greatest activity). The classical pathway can also occur as an innate

Role of Complement Activation during COVID-19

There have been several reports on the role of complement in COVID-19 disease in humans, all focused on innate complement activation that occurs during acute infection. These studies generally conclude that excess complement activity can contribute to severe disease pathology (Table 1). Indeed, serum concentrations of C3 have been reported to be lower in COVID-19 patients compared to healthy controls, possibly reflective of protein activation and cleavage into the C3a component – found at

Lessons on Immunity from Other Human Pathogens

In some studies, innate complement activation and inflammation have also been implicated in the pathology of SARS [32., 33., 34., 35., 36.], caused by SARS-CoV-1, and closely related to SARS-CoV-2. This might occur through MBL binding to the virus, which appears to be neutralizing, but could also lead to complement activation and downstream inflammation [32]. Overall, there is no clear consensus on the role of MBL in SARS [32,33], and the evidence that complement is hyperactive during the acute

Complement-Based Therapeutics

Inhibitors targeting the early stages of complement activation have been used in small case studies to treat COVID-19. These include a case series of a C1-inhibitor in noncritical COVID-19 patients (conestat alfa, n = 5) and a MASP2-inhibitor in severe COVID-19 patients with ARDS (naroplimab, n = 6), whereby all patients had recovered and were discharged from the hospital by days 22 and 91, respectively [47,48]. The C3 inhibitor, AMY-101, was also shown to improve clinical outcomes in COVID-19

Exploiting Complement for Antibody Therapeutics and Vaccines

Many licensed viral vaccines elicit neutralizing antibodies, and are needed for protective immunity [62]. Complement can significantly enhance antibody neutralization [6], and consequently, we posit that it should be considered when developing antibody-based therapeutics and vaccines against SARS-CoV-2 (Figure 1). Presumably, enhanced neutralization might result from the antibody–C1q complex being larger and more effective at blocking receptor–ligand interactions than antibody alone, or

Concluding Remarks

Complement has multiple roles in immunity, including innate and adaptive responses. While excess complement activation has been implicated in severe COVID-19 disease pathology, data supporting this role, or the benefit of complement inhibitors, remain limited (see Outstanding Questions). Importantly, the potential involvement of complement factors in protective immunity has been largely ignored for SARS-CoV-2, but has been defined with other viruses, bacteria, and protozoa. Results from small

Acknowledgments

The authors were supported by funding from the National Health and Medical Research Council of Australia (grants 1173046, 1092789). Burnet Institute is supported by the NHMRC Independent Research Institute Infrastructure Support Scheme and a Victorian State Government Operational Infrastructure grant.

Glossary

Acute infection
initial exposure to pathogen; often characterized by the rapid onset of clinical symptoms.
Acute respiratory distress syndrome
characterized by acute respiratory failure and often associated with inflammation in the lungs.
Adaptive immune response
slowly acquired immune response that is highly specific to the target pathogen often characterized by the production of antigen-specific antibodies.
Angiotensin converting enzyme 2
host ligand for the SARS-CoV-2 spike protein; the former is

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