The COVID-19 Textbook


SECTION 3 • Immunology

correlates of protection analyses pointed to peak immune nAb titers as a key predictor of protection against severe disease. 112,119-121 As mentioned previously, new variants of concern (VOCs) able to evade nAbs arose and continue to arise regularly, with the virus perpetually evolving to evade both infection- and vaccine-induced nAbs. 105-110 Against these VOCs, however, vaccinated individuals still show reduced morbidity and mor tality, 122-124 suggesting that additional immunologic mechanisms, beyond nAbs, contribute to protection against disease and death. Analyses from both preclinical and clinical studies point to a role for T-cell im munity and non-neutralizing, Fc-effector functions in protection against nAb-resistant VOCs. 125-128 T-cell responses are more resistant to mutations in the S protein, 129,130 suggesting that these cells could contribute to durable control of VOCs. Moreover, patients lacking antibodies, because of natural or chemothera peutically induced agammaglobulinemia, did not experience more severe COVID-19 131,132 , suggesting that T cells likely play a compensatory role in viral control after infection. However, T-cell depletions in animal models did not lead to loss of control of virus (measured by viral replication rates) in the lung, 133 suggesting that other, antibody-mediated mechanisms likely control and clear the virus after transmission. Binding antibodies, able to drive antibody effector functions, are also more resilient to viral evolution and recognize VOCs, 134,135 and the passive delivery of sub-nAbs with robust Fc-effector function significantly attenuated viral replication in the lung and led to faster clearance of infection. 136 This suggests that both non-nAb functions and T cells likely collaborate to attenuate disease if transmission occurs. Vaccine boosting has been shown to confer transient protection from infection and provides enhanced protection against mortality in vulnerable populations, 137,138 although breakthrough in fections can occur after boosting. 139 Beyond increased nAb titers, boosting can expand the breadth of variants covered by a vaccine-induced nAb response. 140 Emerging data suggest that boosting with combinations of antigens or with heterologous antigens can lead to a potent diversification of neu tralization and potentially provide protection against a broader array of variants. 141 Boosting also increases T-cell response and Fc-effector-inducing antibodies that may also contribute to longer-term protection against severe disease and death. Thus, beyond the impact of simply raising more antibod ies, boosting can also play a critical part in driving enhanced breadth and T-cell quality, which could ultimately have an important impact on response to future evolving VOCs. Although overall approved vaccines confer robust protection against disease, with boosting help ing to increase that protection, breakthrough disease continues to occur. Next-generation vaccines that can induce high titers of persistent, broadly reactive nAb, protecting against both disease and infection, are required. Despite major successes in vaccine and therapeutic development, the transition of SARS-CoV-2 to endemicity points to a need to evolve new therapeutics and vaccines to tackle this evolving pathogen. However, the pandemic has taught us that nAb activity is partly but perhaps not the sole mechanism by which antibodies confer protection against SARS-CoV-2. Both vaccine and therapeutic development must look beyond traditional design strategies to leverage the full spectrum of antiviral functionality held within the humoral immune response. Critically, the COVID-19 pandemic led to the collection of terabytes upon terabytes of antibody evolution, viral evolution, clinical, and genomic data, offering a unique opportunity to apply machine learning and artificial intelligence to define the rules by which antibodies may be fully used to fight COVID-19 and beyond. Current and future researchers will need to address a variety of issues, outlined later, in order to continue combating this and future pandemics. VARIANTS OF CONCERN The rapid evolution of VOCs across different parts of the globe, durability concerns, and immune-deficient or aging immunity represent major challenges in the transition of vaccine design from one intended to control an ongoing pandemic to one able to provide population-level immu nity against an evolving, endemic virus. 142 NEXT-GENERATION VACCINE CHALLENGES FOR COVID AND BEYOND

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